Solid salt form of alpha-6-mpeg6-o-hydroxycodone as opioid agonists and uses thereof

ABSTRACT

Solid forms of certain opioid agonists are provided herein. Methods of preparing the solid forms, methods of using the solid forms, and pharmaceutical compositions comprising the solid forms are also provided herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/439,473, filed 29 Apr. 2015, which is a 35 U.S.C. §371 application ofInternational Application No. PCT/US2013/067273, filed 29 Oct. 2013,designating the United States, which claims the benefit of priorityunder 35 U.S.C. §119(e) to U.S. Provisional Patent Application Ser. No.61/791,894, filed on 15 Mar. 2013, and U.S. Provisional PatentApplication Ser. No. 61/720,259, filed on 30 Oct. 2012, the disclosuresof which are incorporated by reference in their entireties.

Solid forms of certain opioid agonists are provided herein. Methods ofpreparing the solid forms, methods of using the solid forms, andpharmaceutical compositions comprising the solid forms are also providedherein.

Pain is the most common side effect for which patients seek medicalattention. Opioid analgesics have long been considered the best optionfor effectively treating pain. While useful to manage and treat pain,many opioids are associated with serious central nervous system (CNS)side effects. Such side effects include, but are not limited to,respiratory depression, sedation, and abuse liability. The risk of abuseand overdose is high, as several U.S. agencies, including the Center forDisease Control (CDC), the Food and Drug Administration, and the WhiteHouse, consider prescription opioid analgesics to be at the center of apublic health crisis in the United States. CDC Mortality and MorbidityReport (Jan. 13, 2012), vol. 61, no. 1, pp. 10-13.

In an attempt to address the CNS side effects associated with opioids,certain novel opioid agonists have been developed. U.S. PatentApplication Publication No. 2010/0048602; U.S. Patent ApplicationPublication No. 2011/0237614; U.S. Patent Application Publication No.2012/0184581, and U.S. Patent Application Publication No. 2013/0023553.These compounds are believed to, among other things, maintain analgesicproperties while entering the CNS at a slower rate than existingopioids. Particularly, these compounds are believed to act as mu opioidagonists.

In part of moving these opioid agonists forward as a drug candidate, itis important to understand if such compounds exist in solid forms. Asolid form of a drug substance is often advantageous when developing andformulating a drug product. At the very least, a solid form can aid inthe ease of handling of the drug product and in certain instancesprovide advantageous properties over the non-solid form. Often times,for example, the stability of a solid form is improved over the liquidform. Currently, α-6-mPEG₆-O-hydroxycodone in the freebase form existsas a viscous liquid and no solid form has been prepared to date. Whilethe liquid form may be usable, it would clearly be desirable to have asolid form of α-6-mPEG₆-O-hydroxycodone available as those forms mayhave physicochemical properties that may be used advantageously inpharmaceutical processing and in pharmaceutical compositions.

In certain embodiments, provided herein are one or more solid salt formsof α-6-mPEG₆-O-hydroxycodone.

In certain embodiments, provided herein are methods for preparing one ormore solid salt forms of α-6-mPEG₆-O-hydroxycodone.

In certain embodiments, a pharmaceutical composition is provided,wherein the pharmaceutical composition comprises at least one solid saltform of α-6-mPEG₆-O-hydroxycodone and optionally at least onepharmaceutically acceptable excipient.

In certain embodiments, a method of preparing a free flowing solidcomprising an opioid agonist is provided.

In certain embodiments, a method of treating pain in a patient isprovided, the method comprising administering a solid salt form ofα-6-mPEG₆-O-hydroxycodone.

In certain embodiments, a method of treating pain in a patient isprovided, the method comprising administering a pharmaceuticalcomposition comprising at least one solid salt form ofα-6-mPEG₆-O-hydroxycodone and optionally at least one pharmaceuticallyacceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an XRPD (X-Ray Powder Diffraction) pattern for the solidα-6-mPEG₆-O-hydroxycodone phosphate salt prepared according to Example1.

FIG. 2 is a 1H NMR of the solid α-6-mPEG₆-O-hydroxycodone phosphate saltprepared according to Example 1, taken in DMSO.

FIG. 3 is a thermogravimetirical analysis (TGA) of the solidα-6-mPEG₆-O-hydroxycodone phosphate salt prepared according to Example1.

FIG. 4 is a differential scanning calorimetry (DSC) analysis of thesolid α-6-mPEG₆-O-hydroxycodone phosphate salt prepared according toExample 1.

FIG. 5 is an XRPD pattern for the solid α-6-mPEG₆-O-hydroxycodonephosphate salt (˜900 mg scale) prepared according to Example 1.

FIG. 6 is a differential scanning calorimetry (DSC) analysis of thesolid α-6-mPEG₆-O-hydroxycodone phosphate salt (˜900 mg scale) preparedaccording to Example 1.

FIG. 7 is an XRPD pattern of the solid α-6-mPEG₆-O-hydroxycodoneD-tartaric acid salt as prepared according to Example 1.

FIG. 8 is a 1H NMR of the solid α-6-mPEG₆-O-hydroxycodone D-tartaricacid salt prepared according to Example 1, taken in DMSO.

FIG. 9 is a thermogravimetirical analysis (TGA) of the solidα-6-mPEG₆-O-hydroxycodone D-tartaric acid salt prepared according toExample 1.

FIG. 10 is a differential scanning calorimetry (DSC) analysis of thesolid α-6-mPEG₆-O-hydroxycodone D-tartaric acid salt prepared accordingto Example 1.

FIG. 11 is a 1H NMR of the solid α-6-mPEG₆-O-hydroxycodone phosphatesalt prepared according to Example 3, taken in CDCl₃.

FIG. 12 is a XRPD pattern of the solid α-6-mPEG₆-O-hydroxycodoneD-tartaric acid salt as prepared according to Example 4.

FIG. 13 is a plot of the particle size distribution for a 30 g lot ofthe α-6-mPEG₆-O-hydroxycodone phosphate salt prepared according toExample 7.

FIG. 14 is a plot of the particle size distribution for a 100 g lot ofthe α-6-mPEG₆-O-hydroxycodone phosphate salt prepared according toExample 7.

FIG. 15 is a plot of the particle size distribution for a 520 g lot ofthe α-6-mPEG₆-O-hydroxycodone phosphate salt prepared according toExample 7.

FIG. 16 is a XRPD pattern of solid α-6-mPEG₆-O-hydroxycodone phosphatesalts prepared according to Examples 3 and 7.

FIG. 17 is a plot of the particle size distribution for the solidα-6-mPEG₆-O-hydroxycodone phosphate salts prepared according to Examples3 and 7.

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below. Generally, the nomenclature used herein andthe laboratory procedures in organic chemistry, medicinal chemistry, andpharmacology described herein are those well-known and commonly employedin the art. Unless defined otherwise, all technical and scientific termsused herein generally have the same meaning as commonly understood toone of ordinary skill in the art to which this disclosure belongs.

As used herein, the term “α-6-mPEG₆-O-hydroxycodone,” “PEG₆-Oxycodol,”and “mPEG₆-O-hydroxycodone” are used to refer to a compound of theformula:

which, unless otherwise stated or apparent from the context in which itis used, means in its free base form. A salt ofα-6-mPEG₆-O-hydroxycodone, as understood by one of skill in the art, isan ionic form of the α-6-mPEG₆-O-hydroxycodone that exists with acounterion produced from, in this case, an acid. The counterion producedfrom the acid is variously referred to herein as an “acid counterion” or“counterion.” When, for example, the acid counterion is phosphoric acid,the α-6-mPEG₆-O-hydroxycodone salt is a phosphate salt or phosphoricacid salt. When, for example, the acid counterion is D-tartaric acid,the α-6-mPEG₆-O-hydroxycodone salt is a D-tartaric acid salt or aD-tartrate salt.

While not intending to be limited by any theory or mechanism, it isbelieved that an ionic species of α-6-mPEG₆-O-hydroxycodone may includespecies where the nitrogen accepts a proton, having the formula:

As used herein, and unless otherwise specified, the terms “about” and“approximately,” when used in connection with doses, amounts, or weightpercent of ingredients of a composition or a dosage from, mean a dose,amount, or weight percent that is recognized by those of ordinary skillin the art to provide a pharmacological effect equivalent to thatobtained from the specified dose, amount, or weight percent.Specifically, the terms “about” and “approximately,” when use in thiscontext, contemplate a dose, amount, or weight percent within 15%,within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, orwithin 0.5% of the specified dose, amount, or weight percent.

As used herein, and unless otherwise specified, the terms “about” and“approximately,” when used in connection with a numeric value or rangeof values which is provided to described a particular solid form, e.g.,a specific temperature or temperature range, such as, for example, thatdescribing a melting, dehydration, desolvation or glass transition; amass change, such as, for example, a mass change as a function oftemperature or humidity; a solvent or water content, in terms of, forexample, mass or a percentage; or a peak position, such as for example,in analysis by, for example, differential scanning calorimetry (DSC),thermogravimetric analysis (TGA), or powder X-ray powder diffraction(XRPD); indicate that the value or range of values may deviate to anextent deemed reasonable to one of ordinary skill in the art while stilldescribing the particular solid form. Specifically the terms “about” and“approximately,” when used in this context, indicate that the numericvalue or range of values may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%,0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the recited value orrange while still describing the particular solid form.

The term “solid form” refers to a form of a chemical compound, includinga salt of that compound (e.g. a solid salt form), that exists as asolid. Solid forms may include, for example, crystalline forms,disordered crystalline forms, mesophasic forms, and amorphous forms.

The term “amorphous” or “amorphous form” is intended to mean that thesubstance, component, or product in question is not substantiallycrystalline as determined, for example, by XRPD or where the substance,component, or product in question, for example is not birefringent whenviewed microscopically. In certain embodiments, a sample comprising anamorphous form of a substance may be substantially free of otheramorphous forms and/or crystalline forms.

The term “crystalline form” or “crystal form” refers to a crystallinesolid form of a chemical compound, including, but not limited to, asingle-component or multiple-component crystal form, e.g., a polymorphof a compound; or a solvate, a hydrate, a clathrate, a cocrystal, a saltof a compound, disordered crystalline forms, or a polymorph thereof.“Crystal forms” and related terms herein refer to the variouscrystalline modifications of a given substance, including, but notlimited to, polymorphs, solvates, hydrates, co-crystals, and othermolecular complexes, as well as salts, solvates of salts, hydrates ofsalts, other molecular complexes of salts, and polymorphs thereof.Crystal forms of a substance can be obtained by a number of methods, asknown in the art. Such methods include, but are not limited to, meltrecrystallization, melt cooling, solvent recrystallization,recrystallization in confined spaces such as, e.g., in nanopores orcapillaries, recrystallization on surfaces or templates such as, e.g.,on polymers, recrystallization in the presence of additives, such as,e.g., co-crystal counter-molecules, desolvation, dehydration, rapidevaporation, rapid cooling, slow cooling, vapor diffusion, sublimation,reaction crystallization, antisolvent addition, grinding andsolvent-drop grinding.

The term “mesophasic” or “mesophasic form” refers to a form of achemical compound that in an intermediate state between solid andliquid.

The term “disordered crystalline” refers to a solid form that hascharacteristics of a crystal but lacks the long range order of a purelycrystalline material.

Techniques for characterizing solid forms and amorphous forms include,but are not limited to, thermal gravimetric analysis (TGA), meltingpoint analysis, differential scanning calorimetry, vibrationalspectroscopy, e.g. infrared (IR) and Raman spectroscopy, solid stateNMR, X-ray powder diffraction, optical microscopy, hot stage opticalmicroscopy, scanning electron microscopy (SEM), electron crystallographyand quantitative analysis, particle size analysis (PSA), surface areaanalysis, solubility studies, and dissolution studies.

As used herein and unless otherwise indicated, the term “hydrate” meansa compound or salt thereof, further including a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces. As used herein and unless otherwise indicated, the term“solvate” means a solvate formed from the association of one or moresolvent molecules to a compound provided herein. The term “solvate”includes hydrates (e.g. monohydrate, dihydrate, trihydrate,tetrahydrate, and the like).

The term “pharmaceutically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluents, solvent, or encapsulating material. Incertain embodiments, each component is “pharmaceutically acceptable” inthe sense of being compatible with the other ingredients of apharmaceutical formulation, and suitable for use in contact with thetissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. See,e.g., Remington: The Science and Practice of Pharmacy, 21^(st) ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook ofPharmaceutical Excipients, 6^(th) ed.; Rowe et al., Eds.; ThePharmaceutical Press and the American Pharmaceutical Association: 2009,Handbook of Pharmaceutical Additives, 3^(rd) ed.; Ash and Ash Eds.;Gower Publishing Company: 2007; Pharmaceutical Preformulation andFormulation, 2^(nd) ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla.,2009.

The term “polymorph” or “polymorphic form” refers to one of two or morecrystal forms that comprise the same molecule, molecules or ions.Different polymorphs may have different physical properties such as, forexample, melting temperatures, heats of fusion, solubilities,dissolution rates, and/or vibrational spectra as a result of thearrangement or conformation of the molecules or molecules or ions in thecrystal lattice. The differences in physical properties exhibited bypolymorphs may affect pharmaceutical parameters, such as storagestability, compressibility, density (important in formulation andproduct manufacturing), and dissolution rate (an important factor inbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform disclolors more rapidly when comprised of one polymorph than whencomprised of another polymorph), mechanical changes (e.g. tabletscrumble on storage as a kinetically favored polymorph converts tothermodynamically more stable polymorph), or both (e.g., tablets of onepolymorph are more susceptible to breakdown at high humidity). As aresult of solubility/dissolution differences, in the extreme case, somepolymorphic transitions may result in lack of potency or, at the otherextreme, toxicity. In addition, the physical properties of a crystallineform may be important in processing; for example, one polymorph might bemore likely to form solvates or might be difficult to filter and washfree of impurities (e.g., particle shape and size distribution might bedifferent between polymorphs).

As used herein and unless otherwise indicated, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Incertain embodiments stereomerically pure α-6-mPEG₆-O-hydroxycodone orsalt thereof (including solid salt forms) is provided herein that issubstantially free of other stereoisomers including, for example,β-6-mPEG₆-O-hydroxycodone or salts thereof. In certain embodiments, astereomerically pure compound or salt thereof comprises greater thanabout 80 percent by weight of one stereoisomer of the compound and lessthan about 20 percent by weight of other stereoisomers of the compound,greater than about 90 percent by weight of one stereoisomer of thecompound and less than about 100 percent by weight of otherstereoisomers of the compound, greater than about 95 percent by weightof one stereoisomer of the compound and less than about 5 percent byweight of other stereoisomers of the compound, greater than about 97percent by weight of one stereoisomer of the compound and less thanabout 3 percent by weight of other stereoisomers of the compound,greater than about 99 percent by weight of one stereoisomer of thecompound and less than about 1 percent by weight of other stereoisomersof the compound. In certain embodiments, the term “stereomerically pure”α-6-mPEG₆-O-hydroxycodone means that the compound is made up ofapproximately 100% by weight of α-6-mPEG₆-O-hydroxycodone. The abovepercentages are based on the total amount of combined stereoisomers ofthe compound.

As used herein, a solid form that is “pure,” i.e., substantially free ofother solid forms, contains less than about 15 percent by weight of oneor more other solid forms, less than about 10 percent by weight of oneor more other solid forms, less than about 5 percent by weight of one ormore other solid forms, less than about 3 percent by weight of one ormore other solid forms, less than about 1 percent by weight of one ormore other solid forms, or less than about 0.5 percent by weight of oneor more other solid forms. In certain embodiments, as used herein,“substantially pure” α-6-mPEG₆-O-hydroxycodone salt or a solid formthereof can mean free of organic impurities, for example, unreactedprecursors and side products or oxidative degradation products thatmight be present in the process for preparing α-6-mPEG₆-O-hydroxycodonefree base, or storing α-6-mPEG₆-O-hydroxycodone free base. Organicimpurities can include, for example, α-6-hydroxycodone,α-6-hydroxycodone conjugated to 3, 4, 5, 7, 8, 9, or 10 polyethyleneglycol subunits (i.e. ethylene oxide monomers), and so forth. Anoxidative degradation product of α-6-mPEG₆-O-hydroxycodone free basecan, for instance, be the N-oxide of the free base. As such, a“substantially pure” solid form of α-6-mPEG₆-O-hydroxycodone salt maycomprise, in certain embodiments, less than about 10%, 5%, 3%, 2%, 1%,0.75%, 0.5%, 0.25%, or 0.1% by weight of one or more other solid formsof the compound and/or other chemical compounds. In certain embodiments,a solid form of α-6-mPEG₆-O-hydroxycodone salt that is substantiallypure is substantially free of one or more salt forms, amorphous forms,and/or other chemical compounds.

The term “patient,” “subject,” and “individual” as used herein areinterchangeable and refer to a living organism suffering from or proneto a condition that can be prevented or treated by administration of acompound of the invention as described herein, and includes both humansand animals. Such a condition includes pain, for example, nociceptivepain.

The terms “treat,” “treating,” and “treatment,” as used herein withreference to α-6-mPEG₆-O-hydroxycodone and solid salt forms thereof, aremeant to include alleviation of a condition or symptoms of a condition,for example alleviation of pain or abrogating pain.

The terms “prevent,” “preventing,” and “prevention,” as used herein withreference to α-6-mPEG₆-O-hydroxycodone and solid salt forms thereof, aremeant to include decreasing the likelihood of occurrence of a conditionor symptoms of a condition, for example decreasing the likelihood ofoccurrence of pain or decreasing the severity of pain.

The term “therapeutically effective amount” is meant to include theamount of α-6-mPEG₆-O-hydroxycodone including solid salts forms thereofthat, when administered to a subject, is sufficient to prevent pain tosome extent, reduce pain, to treat pain, and/or alleviate pain, in thesubject when administered.

In certain embodiments, a solid salt form of anα-6-mPEG₆-O-hydroxycodone is provided. In certain embodiments, the solidsalt form of α-6-mPEG₆-O-hydroxycodone is a disordered crystalline form.In certain embodiments, the solid salt form of α-6-mPEG₆-O-hydroxycodoneis a crystalline form. In certain embodiments, the solid salt form ofα-6-mPEG₆-O-hydroxycodone is a mesophasic form. In certain embodiments,the solid salt form is an α-6-mPEG₆-O-hydroxycodone phosphate salt. Incertain embodiments, the solid salt form is an α-6-mPEG₆-O-hydroxycodoneD-tartrate salt.

In certain embodiments, an α-6-mPEG₆-O-hydroxycodone phosphate salt isprovided. In certain embodiments, a solid salt form of anα-6-mPEG₆-O-hydroxycodone phosphate salt is provided. In certainembodiments, the solid salt form of an α-6-mPEG₆-O-hydroxycodonephosphate salt is a mesophasic form. In certain embodiments, the solidsalt form of an α-6-mPEG₆-O-hydroxycodone phosphate salt is in adisordered crystalline form. In certain embodiments, the solid salt formof an α-6-mPEG₆-O-hydroxycodone phosphate salt is in a crystalline form.

In certain embodiments, the solid α-6-mPEG₆-O-hydroxycodone phosphatesalt form is a monophosphate salt. That is, the phosphate anion andα-mPEG₆-O-hydroxycodone cation are present in about a 1:1 ratio.

In certain embodiments, the solid α-6-mPEG₆-O-hydroxycodone salt formprovided herein (e.g. a phosphate or D-tartrate salt) in a substantiallypure form. For example, in certain embodiments a solidα-6-mPEG₆-O-hydroxycodone salt can have a purity of at least about 84%,at least about 85%, at least about 90%, at least about 95%, at leastabout 97%, at least about 98%, at least about 99%, at least about 99.2%,at least about 99.5%, at least about 99.6%, at least about 99.7% or atleast about 99.8% by weight of a single solid form, the remainder of thetotal weight which may be other solid forms and/or other compounds (suchas, for example, an oxidative degradation product).

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has X-ray powder diffraction two theta peak valuessubstantially similar to those of FIG. 1.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has X-ray powder diffraction two theta peak valuessubstantially similar to any one of those of FIG. 16.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has X-ray powder diffraction peak values comprising:2.0±0.2, 15.0±0.2, and 17.0±0.2 degrees two theta, when measured with CuKα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has X-ray powder diffractionpeak values comprising: 2.0±0.2, 5.5±0.2, 15.0±0.2, 17.0±0.2, and20.5±0.2 degrees two theta, when measured with Cu Kα radiation. Incertain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has X-ray powder diffraction peak values comprising:2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degreestwo theta, when measured with Cu Kα radiation. In certain embodiments,the solid form of α-6-mPEG₆-O-hydroxycodone phosphate salt has X-raypowder diffraction peak values comprising: 2.0±0.2, 4.5±0.2, 5.5±0.2,6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 17.5±0.2,19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 28.5±0.2,and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has at least one X-ray powder diffraction peak valueselected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2,11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2,28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kαradiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least two X-ray powderdiffraction peak values selected from the group comprising: 2.0±0.2,5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2,19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta,when measured with Cu Kα radiation. In certain embodiments, the solidform of α-6-mPEG₆-O-hydroxycodone phosphate salt has at least threeX-ray powder diffraction peak values selected from the group comprising:2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degreestwo theta, when measured with Cu Kα radiation. In certain embodiments,the solid form of α-6-mPEG₆-O-hydroxycodone phosphate salt has at leastfour X-ray powder diffraction peak values selected from the groupcomprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2degrees two theta, when measured with Cu Kα radiation. In certainembodiments, the solid form of α-6-mPEG₆-O-hydroxycodone phosphate salthas at least five X-ray powder diffraction peak values selected from thegroup comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2,13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2,and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. Incertain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has at least six X-ray powder diffraction peak valuesselected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2,11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2,28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kαradiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least seven X-ray powderdiffraction peak values selected from the group comprising: 2.0±0.2,5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2,19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta,when measured with Cu Kα radiation. In certain embodiments, the solidform of α-6-mPEG₆-O-hydroxycodone phosphate salt has at least eightX-ray powder diffraction peak values selected from the group comprising:2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degreestwo theta, when measured with Cu Kα radiation. In certain embodiments,the solid form of α-6-mPEG₆-O-hydroxycodone phosphate salt has at leastnine X-ray powder diffraction peak values selected from the groupcomprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2degrees two theta, when measured with Cu Kα radiation. In certainembodiments, the solid form of α-6-mPEG₆-O-hydroxycodone phosphate salthas at least ten X-ray powder diffraction peak values selected from thegroup comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2,13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2,and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. Incertain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has at least eleven X-ray powder diffraction peak valuesselected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2,11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2,28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kαradiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least twelve X-raypowder diffraction peak values selected from the group comprising:2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degreestwo theta, when measured with Cu Kα radiation. In certain embodiments,the solid form of α-6-mPEG₆-O-hydroxycodone phosphate salt has at leastthirteen X-ray powder diffraction peak values selected from the groupcomprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2degrees two theta, when measured with Cu Kα radiation.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has at least one X-ray powder diffraction peak valueselected from the group comprising: 2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2,8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2,20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2degrees two theta, when measured with Cu Kα radiation. In certainembodiments, the solid form of α-6-mPEG₆-O-hydroxycodone phosphate salthas at least two X-ray powder diffraction peak values selected from thegroup comprising: 2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2,13.0±0.2, 15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2,24.0±0.2, 25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta,when measured with Cu Kα radiation. In certain embodiments, the solidform of α-6-mPEG₆-O-hydroxycodone phosphate salt has at least threeX-ray powder diffraction peak values selected from the group comprising:2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2,25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least four X-ray powderdiffraction peak values selected from the group comprising: 2.0±0.2,4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2,26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured withCu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least five X-ray powderdiffraction peak values selected from the group comprising: 2.0±0.2,4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2,26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured withCu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least six X-ray powderdiffraction peak values selected from the group comprising: 2.0±0.2,4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2,26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured withCu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least seven X-ray powderdiffraction peak values selected from the group comprising: 2.0±0.2,4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2,26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured withCu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least eight X-ray powderdiffraction peak values selected from the group comprising: 2.0±0.2,4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2,26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured withCu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least nine X-ray powderdiffraction peak values selected from the group comprising: 2.0±0.2,4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2,26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured withCu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least ten X-ray powderdiffraction peak values selected from the group comprising: 2.0±0.2,4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2,26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, when measured withCu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least eleven X-raypowder diffraction peak values selected from the group comprising:2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2,25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least twelve X-raypowder diffraction peak values selected from the group comprising:2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2,25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least thirteen X-raypowder diffraction peak values selected from the group comprising:2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2,25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least fourteen X-raypowder diffraction peak values selected from the group comprising:2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2,25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least fifteen X-raypowder diffraction peak values selected from the group comprising:2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2,25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least sixteen X-raypowder diffraction peak values selected from the group comprising:2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2,25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least seventeen X-raypowder diffraction peak values selected from the group comprising:2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2,25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has at least eighteen X-raypowder diffraction peak values selected from the group comprising:2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2,25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt exhibits a first broad endothermic peak over a range ofabout 10° C. to about 140° C.; a second endothermic peak at about 160°C. to about 164° C. and a third endothermic peak at about 170° C. toabout 173° C. on a differential scanning calorimeter.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt exhibits an endothermic peak as measured by adifferential scanning calorimeter with an onset of about 174° C. toabout 179° C. and a peak from about 177° C. to about 181° C. in certainembodiments, the solid form of α-6-mPEG₆-O-hydroxycodone phosphate saltexhibits an endothermic peak as measured by a differential scanningcalorimeter with an onset of about 175° C. to about 178° C. and a peakfrom about 178° C. to about 180° C.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has a particle size distribution wherein DV[10] is about3 μm to about 15 μm; DV[50] is about 40 μm to about 60 μm; and DV[90] isabout 90 μm to about 120 μm. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has a particle sizedistribution wherein DV[10] is about 5 μm to about 13 μm; DV[50] isabout 45 μm to about 55 μm; and DV[90] is about 90 μm to about 115 μm.In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has a particle size distribution wherein DV[10] is about6 μm to about 11 μm; DV[50] is about 45 μm to about 55 μm; and DV[90] isabout 90 μm to about 112 μm. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has a particle sizedistribution wherein DV[10] is about 7 μm to about 9 μm; DV[50] is about47 μm to about 53 μm; and DV[90] is about 92 μm to about 109μm. As isunderstood by one of skill in the art a DV[Y] value represents that “Y”percent of the volume distribution is below the particular sizereferenced. For example, DV[10] of about 100 μm indicates that 10percent of the volume distribution is less than about 100 μm.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has a particle size distribution wherein DV[10] is about3 μm to about 15 μm; in certain embodiments, DV[10] is about 5 μm toabout 13 μm; in certain embodiments, DV[10] is about 6 μm to about 11μm; and in certain embodiments, DV[10] is about 7 μm to about 9 μm. Incertain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt has a particle size distribution wherein DV[50] is about40 μm to about 60 μm; in certain embodiments, DV[50] is about 45 μm toabout 55 μm; and in certain embodiments, DV[50] is about 47 μm to about53 μm. In certain embodiments, the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate salt has a particle sizedistribution wherein DV[90] is about 90 μm to about 120 μm; in certainembodiments, DV[90] is about 90 μm to about 115 μm; in certainembodiments, DV[90] is about 90 μm to about 112 μm; and in certainembodiments, DV[90] is about 92 μm to about 109 μm.

In certain embodiments the solid form of α-6-mPEG₆-O-hydroxycodonephosphate salt is prepared by dissolving α-6-mPEG₆-O-hydroxycodone freebase in a mixture of a first solvent and a second solvent; combining theα-6-mPEG₆-O-hydroxycodone solution with a solution of phosphoric acid ina third solvent and fourth solvent; combining theα-6-mPEG₆-O-hydroxycodone phosphoric acid solution with a fifth solventand a sixth solvent to form a slurry; and filtering the slurry to yieldthe α-6-mPEG₆-O-hydroxycodone phosphate salt in solid form. In certainembodiments, the first solvent is methanol and the second solvent istert-butyl methyl ether (tBME, MTBE). In certain embodiments, the firstsolvent and second solvent are present in a ratio of about 2:1(volume:volume). In certain embodiments, the volume of the mixture ofthe first solvent and the second solvent is about two relative volumes.In certain embodiments, the third solvent is methanol and the fourthsolvent is tert-butyl methyl ether. In certain embodiments, the thirdsolvent and the fourth solvent are present in a ratio of about 2:1(volume:volume). In certain embodiments, the volume of the mixture ofthe third solvent and the fourth solvent is about two relative volumes.In certain embodiments, the volume of the mixture of the third solventand the fourth solvent is about 1.2 relative volumes. In certainembodiments, the fifth solvent is heptanes and the sixth solvent istert-butyl methyl ether. In certain embodiments, the fifth solvent andthe sixth solvent are present in a ratio of about 4:1 (volume:volume).In certain embodiments, the mixture of the fifth solvent and the sixthsolvent is about 14 relative volumes. In certain embodiments, theα-6-mPEG₆-O-hydroxycodone phosphoric acid solution is added to the fifthsolvent and sixth solvent over about 1 to about 3 hours to form theslurry. In certain embodiments, prior to filtering, the supernatantsolvent mixture is removed and additional heptanes are added to thesolid salt form of α-6-mPEG₆-O-hydroxycodone phosphate salt at leastonce. In certain embodiments, the solid salt form ofα-6-mPEG₆-O-hydroxycodone phosphate salt is washed with about 2 relativevolumes of heptanes after filtering.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate is prepared by dissolving α-6-mPEG₆-O-hydroxycodone free basein about 2 relative volumes of a mixture methanol and tert-butyl methylether (2:1 ratio of methanol to tert-butyl methyl ether); combining theα-6-mPEG₆-O-hydroxycodone solution with a solution of phosphoric acid inabout 1.2 relative volumes of a mixture methanol and tert-butyl methylether (2:1 ratio of methanol to tert-butyl methyl ether); combining theα-6-mPEG₆-O-hydroxycodone phosphoric acid solution with about 14relative volumes of a mixture of heptanes and tert-butyl methyl ether(4:1 ratio of heptanes to tert-butyl methyl ether) to form a slurry;optionally removing the supernatant and adding additional heptanes tothe slurry; and filtering the slurry to yield theα-6-mPEG₆-O-hydroxycodone phosphate salt in solid form. In certainembodiments the α-6-mPEG₆-O-hydroxycodone phosphoric acid solution iscombined with the mixture of heptanes and tert-butyl methyl ether overabout 10 minutes to about 3 hours. In certain embodiments, the slurrycan be distilled to remove portions of the methanol solvent. In certainembodiments, the solid salt form of α-6-mPEG₆-O-hydroxycodone phosphatesalt is washed with about 2 volumes of heptanes after filtering.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodonephosphate is prepared by dissolving α-6-mPEG₆-O-hydroxycodone free basein a mixture of tert-butyl methyl ether and a hydrocarbon solvent;adding phosphoric acid to form a slurry; stirring the slurry, andfiltering to recover the solid α-6-mPEG₆-O-hydroxycodone phosphate salt.In certain embodiments, the hydrocarbon solvent is a hydrocarbon havingfrom 3 to 10 carbon atoms. In certain embodiments, the hydrocarbonsolvent is heptane. In certain embodiments, the hydrocarbon solvent is amixture of isomers of heptane (i.e. heptanes). In certain embodiments,the solid form of α-6-mPEG₆-O-hydroxycodone phosphate is prepared bydissolving α-6-mPEG₆-O-hydroxycodone free base in a mixture oftert-butyl methyl ether and heptanes; adding phosphoric acid to form aslurry; stirring the slurry, and filtering to recover the solidα-6-mPEG₆-O-hydroxycodone phosphate salt. In certain embodiments, thephosphoric acid is added over a time of about 30 minutes to about 3hours. In certain embodiments, the phosphoric acid is added over about 1hour. In certain embodiments, the phosphoric acid is added at about tenminute intervals over the course of about 30 minutes to about 3 hours.In certain embodiments, the phosphoric acid is added at about ten minuteintervals over the course of about 1 hour. In certain embodiments, thesolid α-6-mPEG₆-O-hydroxycodone phosphate salt is washed with tert-butylmethyl ether. In certain embodiments, the solidα-6-mPEG₆-O-hydroxycodone phosphate salt is washed with heptanes. Incertain embodiments, the amount of α-6-mPEG₆-O-hydroxycodone free baseis “X” kilograms. In certain embodiments, the volume of tert-butylmethyl ether is 5*“X” liters and the volume of heptanes is “X” liters.In certain embodiments, the volume to volume ratio of tert-butyl methylether to heptanes is about 5:1. In certain embodiments the amount ofphosphoric acid is about 0.80 molar equivalents to about 1.20 molarequivalents. In certain embodiments, the amount of phosphoric acid isabout 0.90 to about 1.10 molar equivalents. In certain embodiments, theamount of phosphoric acid is about 1.0 molar equivalents. In certainembodiments, the amount of phosphoric acid is about 1.01 molarequivalents. In certain embodiments, the amount of phosphoric acid (kg)is equal to (“n”*“X”) where n is about [(16 to 17)/“assay value ofphosphoric acid”]. In certain embodiments, the amount of phosphoric acid(kg) is equal to “n”*“X” where n is about 16.6/“assay value ofphosphoric acid”. In certain embodiments, the amount of phosphoric acid(kg) is equal to “n”*“X” where n is about 16.614/“assay value ofphosphoric acid”. The “assay value of phosphoric acid” refers to thevalue (w/w %) reported by the manufacturer's analysis. In certainembodiments, the phosphoric acid is an aqueous phosphoric acid solution.In certain embodiments, the aqueous phosphoric acid solution is about an85 percent solution in water. In certain embodiments, after thephosphoric acid has been added, the solution is allowed to stir forabout 1 to about 4 hours. In certain embodiments, after the phosphoricacid has been added, the solution is allowed to stir for about 2 hours.In certain embodiments, the solution of α-6-mPEG₆-O-hydroxycodone freebase is maintained at a temperature of about 15° C. In certainembodiments, the solution of α-6-mPEG₆-O-hydroxycodone is maintained ata temperature of about 15° C. while the phosphoric acid is being added.In certain embodiments, the solution of α-6-mPEG₆-O-hydroxycodone ismaintained at a temperature of about 15° C. throughout the addition ofphosphoric acid. In certain embodiments, the reaction mixture containswater. In certain embodiments, the amount of water is about 0.4-0.8 wt%.

In certain embodiments, the solid α-6-mPEG₆-O-hydroxycodone D-tartratesalt form is a monotartrate salt. That is, the tartrate anion andα-mPEG₆-O-hydroxycodone cation are present in about a 1:1 ratio.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodoneD-tartrate salt has X-ray powder diffraction two theta peak valuessubstantially similar to those of FIG. 7 and/or FIG. 12. In certainembodiments, the solid form of α-6-mPEG₆-O-hydroxycodone D-tartrate salthas X-ray powder diffraction peak values comprising: 2.5±0.2 and15.0±0.2 degrees two theta, when measured with Cu Kα radiation. Incertain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodoneD-tartrate salt has X-ray powder diffraction peak values comprising:2.5±0.2, 15.0±0.2, 20.0±0.2, and 23.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodoneD-tartrate salt exhibits a first broad endothermic peak over a range ofabout 40° C. to about 107° C. and a second endothermic peak at about126° C. on a differential scanning calorimeter.

In certain embodiments, the solid form of α-6-mPEG₆-O-hydroxycodoneD-tartrate is prepared by dissolving α-6-mPEG₆-O-hydroxycodone free basein a first solvent; combining the α-6-mPEG₆-O-hydroxycodone solutionwith a solution of D-tartaric acid in a second solvent; adding a thirdsolvent to the mixture of the α-6-mPEG₆-O-hydroxycodone solution and theD-tartaric acid solution to form a slurry; and filtering the slurry toyield the α-6-mPEG₆-O-hydroxycodone D-tartrate salt in solid form. Incertain embodiments, the first solvent is tetrahydrofuran. In certainembodiments, the volume of the first solvent is about 2 relativevolumes. In certain embodiments, the second solvent is tetrahydrofuran.In certain embodiments, the volume of the second solvent is about 2relative volumes. In certain embodiments, the third solvent is heptanes.In certain embodiments, the volume of the third solvent is about 6relative volumes. In certain embodiments, the third solvent is added tothe mixture of the α-6-mPEG₆-O-hydroxycodone and D-tartaric acidsolution over about 30 minutes.

In certain embodiments the solid form of α-6-mPEG₆-O-hydroxycodoneD-tartrate is prepared by dissolving α-6-mPEG₆-O-hydroxycodone free basein about 2 relative volumes of tetrahydrofuran; combining theα-6-mPEG₆-O-hydroxycodone solution with a solution of D-tartaric acid inabout 2 relative volumes of tetrahydrofuran; adding about 6 equivalentsof heptanes to the α-6-mPEG₆-O-hydroxycodone D-tartaric acid solution toform a slurry; and filtering the slurry to yield theα-6-mPEG₆-O-hydroxycodone D-tartrate salt in solid form. In certainembodiments, the heptanes are added over about 30 minutes. In certainembodiments, the solid α-6-mPEG₆-O-hydroxycodone D-tartrate salt iswashed with about 2 volumes of heptanes after filtering.

It will be recognized that in their solid forms,α-6-mPEG₆-O-hydroxycodone salts provided herein (e.g. phosphate salts)can exhibit desirable characteristics for the preparation, processingand/or storage of a pharmaceutical composition or drug product. As such,in certain embodiments, pharmaceutical compositions are provided thatcomprise a solid α-6-mPEG₆-O-hydroxycodone salt and a pharmaceuticallyacceptable excipient and/or carrier. The choice of excipient, to a largeextent, depends on factors, such as the particular mode ofadministration, the effect of the excipient on the solubility andstability of the active ingredient, and the nature of the dosage form.

Exemplary solids include granules, pellets, beads, powders, which can beadministered “as-is” or formulated into one or more of the following foradministration to a patient: a tablet; a capsule; a caplet; asuppository; and a troche. In certain embodiments, the composition willbe in a unit dosage form to thereby provide a unit dosage suitable forsingle administration of a dosage of α-6-mPEG₆-O-hydroxycodone in theunit dosage form. Suitable pharmaceutical compositions and dosage formsmay be prepared using conventional methods known to those in the fieldof pharmaceutical formulation and described in the pertinent texts andliterature, e.g. Remington: The Science and Practice of Pharmacy,21^(st) edition (Lippincott Williams & Wilkins, Philadelphia, Pa. 2005).

In certain embodiments, the pharmaceutical composition is in an oraldosage form, for example, tablets, capsules, gel caps, suspensions,solutions, elixirs, and syrups, and can also comprise a plurality ofgranules, beads, powders or pellets that are optionally encapsulated.Such dosage forms are prepared using conventional methods known to thosein the field of pharmaceutical formulation and described in thepertinent texts.

Tablets and caplets, for example, can be manufactured using standardtablet processing procedures and equipment. Direct compression andgranulation techniques may be used when preparing tablets or capletscontaining the α-6-mPEG₆-O-hydroxycodone salt forms described herein. Inaddition to the α-6-mPEG₆-O-hydroxycodone salt, the tablets and capletswill generally contain inactive, pharmaceutically acceptable carriermaterials such as binders, lubricants, disintegrants, fillers,stabilizers, surfactants, coloring agents, and the like. Binders areused to impart cohesive qualities to a tablet, and thus ensure that thetablet remains intact. Suitable binder materials include, but are notlimited to, starch (including corn starch and pregelatinized starch),gelatin, sugars (including sucrose, glucose, dextrose and lactose),polyethylene glycol, waxes, and natural and synthetic gums, e.g., acaciasodium alginate, polyvinylpyrrolidone, cellulosic polymers (includinghydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethylcellulose, and the like), and Veegum. Lubricants are used to facilitatetablet manufacture, promoting powder flow and preventing particlecapping (i.e., particle breakage) when pressure is relieved. Usefullubricants are magnesium stearate, calcium stearate, and stearic acid.Disintegrants are used to facilitate disintegration of the tablet, andare generally starches, clays, celluloses, algins, gums, or crosslinkedpolymers. Fillers include, for example, materials such as silicondioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose,and microcrystalline cellulose, as well as soluble materials such asmannitol, urea, sucrose, lactose, dextrose, sodium chloride, andsorbitol. Stabilizers, as well known in the art, are used to inhibit orretard drug decomposition reactions that include, by way of example,oxidative reactions.

In certain embodiments, the tablet can be in the form of a uniformtablet. In uniform tablets the formulation used in preparing the tabletis a substantially homogeneous mixture of one or more active agents andone or more pharmaceutical excipients (e.g., diluents). The formulationis then used to make tablets using a suitable tableting process tothereby result in a tablet that is substantially homogenous throughoutthe tablet.

Capsules are also suitable oral dosage forms, in which case thecomposition may be encapsulated in the form of a liquid, semi-solid orsolid (including particulates such as granules, beads, powders orpellets). Suitable capsules may be either hard or soft, and aregenerally made of gelatin, starch, or a cellulosic material. In certainembodiments the capsules are gelatin. Two-piece hard gelatin capsulesare preferably sealed, such as with gelatin bands or the like. See, forexample, Remington: The Science and Practice of Pharmacy, supra, whichdescribes materials and methods for preparing encapsulatedpharmaceuticals.

Exemplary excipients include, without limitation, those selected fromthe group consisting of carbohydrates, inorganic salts, antimicrobialagents, antioxidants, surfactants, buffers, acids, bases, andcombinations thereof.

A carbohydrate such as a sugar, a derivatized sugar such as an alditol,aldonic acid, an esterified sugar, and/or a sugar polymer may be presentas an excipient. Specific carbohydrate excipients include, for example:monosaccharides, such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, xylitol, maltitol, lactitol, sorbitol(glucitol), pyranosyl sorbitol, myoinositol, and the like.

The excipient can also include an inorganic salt or buffer such ascitric acid, sodium chloride, potassium chloride, sodium sulfate,potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic,and combinations thereof.

The composition may also include an antimicrobial agent for preventingor deterring microbial growth. Nonlimiting examples of antimicrobialagents suitable for the present invention include benzalkonium chloride,benzethonium chloride, benzyl alcohol, cetylpyridinium chloride,chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate,thimersol, and combinations thereof.

An antioxidant can be present in the composition as well. Antioxidantsare used to prevent oxidation, thereby preventing the deterioration ofthe conjugate or other components of the preparation. Suitableantioxidants for use in the present invention include, for example,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorous acid, monothioglycerol, propyl gallate, sodiumbisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, andcombinations thereof.

A surfactant may be present as an excipient. Exemplary surfactantsinclude: polysorbates, such as “Tween 20” and “Tween 80,” and pluronicssuch as F68 and F88 (both of which are available from BASF, Mount Olive,N.J.); sorbitan esters; lipids, such as phospholipids such as lecithinand other phosphatidylcholines, phosphatidylethanolamines (althoughpreferably not in liposomal form), fatty acids and fatty esters;steroids, such as cholesterol; and chelating agents, such as EDTA, zincand other such suitable cations.

Acids or bases may be present as an excipient in the composition.Nonlimiting examples of acids that can be used include those acidsselected from the group consisting of hydrochloric acid, acetic acid,phosphoric acid, citric acid, malic acid, lactic acid, formic acid,trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid,sulfuric acid, fumaric acid, and combinations thereof. Examples ofsuitable bases include, without limitation, bases selected from thegroup consisting of sodium hydroxide, sodium acetate, ammoniumhydroxide, potassium hydroxide, ammonium acetate, potassium acetate,sodium phosphate, potassium phosphate, sodium citrate, sodium formate,sodium sulfate, potassium sulfate, potassium fumerate, and combinationsthereof.

The pharmaceutical compositions encompass all types of formulations. Theamount of the active agent (i.e., solid α-6-mPEG₆-O-hydroxycodone saltform) in the composition will vary depending on a number of factors, butwill optimally be a therapeutically effective dose the active agent whenthe composition is stored in a unit dose form. A therapeuticallyeffective dose for the active agent can be determined experimentally byrepeated administration of increasing amounts of the active agent inorder to determine which amount produces a clinically desired endpoint.In certain embodiments, the amount of a solid salt formα-6-mPEG₆-O-hydroxycodone in the composition is within the range ofabout 5 mg to about 1000 mg. In certain embodiments, the amount of asolid salt form α-6-mPEG₆-O-hydroxycodone in the composition is withinthe range of about 50 mg to about 750 mg. In certain embodiments, theamount of a solid salt form α-6-mPEG₆-O-hydroxycodone in the compositionis within the range of about 100 mg to about 500 mg. In certainembodiments, the amount of a solid salt form α-6-mPEG₆-O-hydroxycodonein the composition is about 20 mg; about 40 mg, about 50 mg; about 80mg; about 100 mg; about 125 mg; about 150 mg; about 200 mg; about 250mg; about 300 mg; about 350 mg; about 400 mg; about 450 mg; or about 500mg.

The amount of any individual excipient in the composition will varydepending on the activity of the excipient and particular needs of thecomposition. Typically, the optimal amount of any individual excipientis determined through routine experimentation, i.e., by preparingcompositions containing varying amounts of the excipient (ranging fromlow to high), examining the stability and other parameters of thecomposition, and then determining the range at which optimal performanceis attained with no significant adverse effects. Exemplary excipientsare described, for instance, in Handbook of Pharmaceutical Excipients,5^(th) Edition (Rowe et al., editors; American PharmaceuticalAssociation Publications, Washington D.C., 2005).

In certain embodiments, a composition may be formed using the free baseform of α-6-mPEG₆-O-hydroxycodone. In certain embodiments, thecomposition is a tablet. The free base form of α-6-mPEG₆-O-hydroxycodoneexists as a viscous liquid at ambient storage conditions. Generally,such materials provide challenges for solid formulations. The free baseform of α-6-mPEG₆-O-hydroxycodone may be converted to a free flowingsolid by submitting α-6-mPEG₆-O-hydroxycodone and certain tabletcomponents to a high speed granulator and mixing. In certainembodiments, the α-6-mPEG₆-O-hydroxycodone free base is added to asuitable solvent (e.g. water, citric acid solution) to provide a flowingliquid; all excipients are charged into a bowl in a high speedgranulator; the solution containing α-6-mPEG₆-O-hydroxycodone is addedto the excipient mixture and mixed; the wet granules are dried; extragranule materials are added and the mixture is further mixed, and themixture is pressed into tablets. In certain embodiments, an aqueoussolution of a binder, such as polyvinyl pyrolidine (PVP), hydroxypropylmethyl cellulose or hypromellose (HPMC), hydroxypropyl cellulose (HPC),etc., is added to the mixture in the high speed granulator and mixed. Incertain embodiments a film coating is added to the final tablets. Incertain embodiments, the maximum drug loading for such tablets is about14 percent. In certain embodiments, the drug loading for the tablet isless than about 20 percent; in certain embodiments the drug loading forthe tablet is less than about 18 percent; in certain embodiments thedrug loading for the tablet is less than about 16 percent; in certainembodiments the drug loading for the tablet is less than about 14percent; in certain embodiments the drug loading for the tablet is lessthan about 12 percent; and in certain embodiments the drug loading forthe tablet is less than about 10 percent.

Example 5 provides exemplary tablets formed with theα-6-mPEG₆-O-hydroxycodone free base.

The formulations prepared using the free base ofα-6-mPEG₆-O-hydroxycodone are unique in that they result in theformation of free flowing granules that have adequate compressibilityand can be formulated, for example, as hard gelatin capsules or tablets.The granules are formed from a viscous liquid (α-6-mPEG₆-O-hydroxycodonefreebase) without the use of adsorbants, antiadherants, and/ordetackifying agents, which may often be employed when working with ahighly viscous substance. Further, the use of an acid, for example,citric acid, resulted in better flow and compressibility when comparedto granules that did not include an acid, for example, citric acid. Assuch, the granules formed demonstrate a means for producing free flowinggranules from a viscous liquid. Tablets formed from those granulesexhibited adequate hardness and friability along with rapiddisintegration. Tables 4-6.

In certain embodiments, a composition may be formed from the solidα-6-mPEG₆-O-hydroxycodone phosphate salt form disclosed herein. Incertain embodiments, the composition is a tablet. In certainembodiments, the solid α-6-mPEG₆-O-hydroxycodone phosphate salt form isconverted to a free flowing solid by submitting the solidα-6-mPEG₆-O-hydroxycodone phosphate salt and certain tablet componentsto a high speed granulator and mixing. In certain embodiments, thetablet comprises intra granular components. In certain embodiments, thetablet comprises intra granular and extra granular components. Incertain embodiments, the solid α-6-mPEG₆-O-hydroxycodone phosphate saltform and solid excipients are added to a bowl in a high speed granulatorand mixed, a solution of a binder, such as polyvinyl pyrolidine (PVP),hyrdoxypropyl methyl cellusoe (HPMC), hydroxypropyl cellulose (HPC),etc. and water is added while mixing, the wet mixture is dried to formdry granules; extra granular materials are added and the mixture isfurther mixed; and the mixture is pressed into tablets. In certainembodiments, a film coating is added to the final tablets. In certainembodiments, the tablet has a drug loading of greater than about 5percent; in certain embodiments greater than about 10 percent; incertain embodiments greater than about 15 percent; in certainembodiments greater than about 20 percent; in certain embodimentsgreater than about 25 percent; in certain embodiments greater than about30 percent; in certain embodiments greater than about 35 percent; incertain embodiments greater than about 40 percent; in certainembodiments greater than about 45 percent. In certain embodiments, thedrug loading is in the range of about 15 percent to about 50 percent. Incertain embodiments, the drug loading is in the range of about 20percent to about 45 percent. In certain embodiments, the drug loading isin the range of about 25 percent to about 40 percent. In certainembodiments, the drug loading is in the range of about 30 percent toabout 40 percent. In certain embodiments, the drug loading is in therange of about 33 percent to about 37 percent. In certain embodiments,the drug loading is about 35 percent. In certain embodiments, the drugloading is about 30 percent. In certain embodiments, the drug loading isabout 25 percent. In certain embodiments, the drug loading is about 26percent. In certain embodiments, the drug loading is about 27 percent.In certain embodiments, the drug loading is about 28 percent. In certainembodiments, the drug loading is about 29 percent. In certainembodiments, the drug loading is about 31 percent. In certainembodiments, the drug loading is about 32 percent. In certainembodiments, the drug loading is about 33 percent. In certainembodiments, the drug loading is about 34 percent.

In certain embodiments of a tablet described herein, the tablet has afriability of less than about 1.0 percent. In certain embodiments, thetablet has a friability of less than about 0.5 percent. In certainembodiments, the tablet has a friability of less than about 0.1 percent.In certain embodiments the tablet has a friability of less than about0.05 percent.

In certain embodiments, the tablet comprises only intragranularcomponents. In certain embodiments, the solid α-6-mPEG₆-O-hydroxycodonephosphate salt form and solid excipients are added to a bowl and blended(e.g. a V-blender), and the mixture is pressed into tablets. In certainembodiments, one of more excipient is selected from the group comprisingdibasic calcium phosphate, microcrystalline cellulose, croscarmellosesodium, colloidal silicon dioxide, and magnesium stearate. Additionalexcipients may also be included. In certain embodiments, the excipientscomprise the group comprising dibasic calcium phosphate,microcrystalline cellulose, croscarmellose sodium, colloidal silicondioxide, and magnesium stearate. In certain embodiments, the filmcoating is added to the tablets. In certain embodiments, the tablet hasa drug loading of greater than about 5 percent; in certain embodimentsgreater than about 10 percent; in certain embodiments greater than about15 percent; in certain embodiments greater than about 20 percent; incertain embodiments greater than about 25 percent; in certainembodiments greater than about 30 percent; in certain embodimentsgreater than about 35 percent; in certain embodiments greater than about40 percent; in certain embodiments greater than about 45 percent. Incertain embodiments, the drug loading is in the range of about 15percent to about 50 percent. In certain embodiments, the drug loading isin the range of about 20 percent to about 45 percent. In certainembodiments, the drug loading is in the range of about 25 percent toabout 40 percent. In certain embodiments, the drug loading is in therange of about 30 percent to about 40 percent. In certain embodiments,the drug loading is in the range of about 33 percent to about 37percent. In certain embodiments, the drug loading is about 35 percent.In certain embodiments, the drug loading is about 30 percent. In certainembodiments, the drug loading is about 25 percent. In certainembodiments, the drug loading is about 26 percent. In certainembodiments, the drug loading is about 27 percent. In certainembodiments, the drug loading is about 28 percent. In certainembodiments, the drug loading is about 29 percent. In certainembodiments, the drug loading is about 31 percent. In certainembodiments, the drug loading is about 32 percent. In certainembodiments, the drug loading is about 33 percent. In certainembodiments, the drug loading is about 34 percent. In certainembodiments of a tablet described herein, the tablet has a friability ofless than about 1.0 percent. In certain embodiments, the tablet has afriability of less than about 0.5 percent. In certain embodiments, thetablet has a friability of less than about 0.1 percent. In certainembodiments the tablet has a friability of less than about 0.05 percent.In certain embodiments the tablet has a friability of less than about0.02 percent.

Examples 6, 8, and 9 provide exemplary tablets formed with the solidα-6-mPEG₆-O-hydroxycodone phosphate salt.

Tablets and compositions of the solid form of theα-6-mPEG₆-O-hydroxycodone tartrate salt may be formed according to themethods known to those of skill in the art, as well as those disclosedabove or the Examples provided below.

Generally, however, the excipient(s) will be present in the compositionin an amount of about 1% to about 99% by weight, in certain embodimentsfrom about 2%-98% by weight, in certain embodiments from about 5-95% byweight of the excipient, and in certain embodiments less than 30% byweight.

In certain embodiments, provided herein is a method for administeringthe solid salt form of α-6-mPEG₆-O-hydroxycodone as described herein. Incertain embodiments, the method comprises administering a composition asprovided herein to a patient suffering from a condition that isresponsive to treatment with an opioid agonist. In certain embodiments,the method comprises administering a unit dosage form described herein.The method of administering may be used to treat any condition that canbe remedied or prevented by administration of the opioid agonist (e.g.,moderate to severe pain). As the cause of the pain is not necessarilycritical to the methods disclosed herein, the methods include thetreatment of pain arising from various sources, injuries, and diseasestates. Those of ordinary skill in the art appreciate which conditionsan opioid agonist can effectively treat, for example, nociceptive pain.In certain embodiments, the condition includes neuropathic pain. Theactual dose administrated will vary depending on the age, weight, andgeneral condition of the subject as well as the severity of thecondition being treated, the judgment of the health care professional,and the active ingredient being administered. Therapeutically effectiveamounts are known to those of skill in the art and/or described in thepertinent reference texts and literature. Generally, a therapeuticallyeffective amount will range from about 0.01 mg to about 750 mg. Incertain embodiments the dose ranges from about 10 mg to about 750 mg. Incertain embodiments the dose ranges from about 50 mg to about 500 mg. Incertain embodiments, the dose ranges from about 5 mg to about 500. Incertain embodiments the dose ranges from about 100 mg to about 500 mg.In certain embodiments the dose ranges from about 150 mg to about 450mg. In certain embodiments, the dose is selected from the groupcomprising about 10 mg; about 20 mg; about 40 mg; about 50 mg; about 80mg; about 100 mg; about 125; about 150; about 160 mg; about 200 mg;about 250 mg; about 300 mg; about 320 mg; about 350 mg; about 400 mg;about 450 mg; and about 500 mg.

The solid salt form of α-6-mPEG₆-O-hydroxycodone, pharmaceuticalcomposition comprising the solid salt form of α-6-mPEG₆-O-hydroxycodone,and/or dosage form (e.g., a unit dosage form) described herein, can beadministered in a variety of dosing schedules depending on the judgmentof the clinician, needs of the patient, and so forth. The specificdosing schedule will be known by those of ordinary skill in the art orcan be determined experimentally using routine methods. Exemplary dosingschedules include, without limitation, administration five times a day,four times a day, three times a day, twice daily, once daily, threetimes weekly, twice weekly, once weekly, twice monthly, once monthly,and any combination thereof. In certain embodiments, the solid salt formof α-6-mPEG₆-O-hydroxycodone is administered as necessary over a 24 hourperiod to manage moderate to severe pain. Management of moderate tosevere pain includes treating and/or preventing pain. In certainembodiments, the solid salt form of α-6-mPEG₆-O-hydroxycodone isadministered as necessary over a 24 hour period to treat and/or preventmoderate to severe pain. In certain embodiments, the solid salt form ofα-6-mPEG₆-O-hydroxycodone is administered as necessary over a 24 hourperiod to treat moderate to severe pain. In certain embodiments, thesolid salt form of α-6-mPEG₆-O-hydroxycodone is administered asnecessary over a 24 hour period to prevent moderate to severe pain. Asis understood by one of skill in the art, administration of the solidsalt form of α-6-mPEG₆-O-hydroxycodone may also include administrationof a pharmaceutical composition comprising the solid salt form ofα-6-mPEG₆-O-hydroxycodone, and/or dosage form composition comprising thesolid salt form of α-6-mPEG₆-O-hydroxycodone (e.g., a unit dosage form).

It is to be understood that while the invention has been described inconjunction with certain embodiments thereof, that the foregoingdescription as well as the experimental that follow are intended toillustrate and not limit the scope of the invention.

EXAMPLES

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., U.S.A.). Routine chemicaland physiological analyses were conducted following standard operatingprocedures known to those skilled in the art. For example, certainanalyses were performed as described in the following paragraphs.

XRPD.

In certain instances, XRPD patterns were collected using an InelXRF-3000 diffractometer equipped with a CPS (Curved Position Sensitive)detector with a °2θ (degree two-theta) range of 120°. Real time datawere collected using Cu-Kα radiation at a resolution of 0.03°2θ. Thetube voltage and amperage were set to 40 kV and 30 mA, respectively. Themonochromator slit was set at 5 mm by 160 μm. The pattern is displayedfrom 2.5-40°2θ. Samples were packed into thin-walled glass capillariesfor analysis. Each capillary was mounted onto a goniometer head that ismotorized to permit spinning of the capillary during data acquisition.Samples were analyzed for 300 seconds. Instrument calibration wasperformed using a silicon reference standard.

In other instances, XRPD patterns were collected on a PANalytical X'PertPrio diffractometer. The samples were analyzed using Cu Kα radiationproduced using an Optix long fine-focus source. An elliptically gradedmultilayer mirror was used to focus the Cu-Kα X-rays of the sourcethrough the specimen and onto the detector. The specimen was sandwichedbetween 3-micron thick films, analyzed in transmission geometry, androtated to optimize orientation statistics. A beamstop was used tominimize the background generated by air scattering. Helium andanti-scatter extension were used. Soller slits were used for theincident and diffracted beams to minimize axial divergence. Thediffraction patterns were collected using a scanning position-sensitivedetector (X'Celerator) located 240 mm from the specimen. Prior to theanalysis a silicon specimen (NIST standard reference material 640c) wasanalyzed to verify the position of the silicon 111 peak.

Thermogravimetric Analysis (TGA).

TGA was performed using a TA Instruments Q5000IR thermogravimetricanalyzer. Each sample was placed in an aluminum sample pan, insertedinto the TG furnace, and accurately weighed. The furnace was heated fromambient temperature under nitrogen at a rate of 10° C./min, up to afinal temperature of 350° C. Nickel and Alumel™ were used as thecalibration.

Differential Scanning Calorimetry (DSC).

DSC analysis was performed using a T A Instruments differential scanningcalorimeter Q2000. Each sample was placed into an aluminum DSC pan, andits weight accurately recorded. Hermetically sealed laser pin hole orlid covered and crimped pan was used. The sample cell was equilibratedat −30° C. and heated under a nitrogen purge at a rate of 10° C./min, upto final temperatures of 200° C. or 250° C. Indium metal was used as thecalibration standard. Reported temperatures are at the transition maximaor as a range.

Moisture Sorption.

Moisture sorption/desorption data were collected on a VTI SGA-1 00 VaporSorption Analyzer. Sorption and desorption data were collected over arange of 5% to 95% relative humidity (RH) at 10% RH intervals under anitrogen purge. Samples were not dried prior to analysis. Equilibriumcriteria used for analysis were less than 0.0100% weight change in 5minutes, with a maximum equilibration time of 3 hours if the weightcriterion was not met. Data were not corrected for the initial moisturecontent of the samples. NaCl and PVP were used as calibration standards.

Nuclear Magnetic Resonance Spectroscopy (NMR).

Solution ¹H-NMR spectra were acquired. Details regarding the scanparameters are included on the relevant figures.

Hotstage Microscopy.

Hot stage microscopy was performed using a Linkam hot stage model FTIR600 equipped with a TMS93 controller and mounted under a Leica DM LPmicroscope. The sample was observed using a 20× objective with crossedpolarizers and a first order red compensator in place during heating ofthe stage. Images were captured using a SPOT Insight™ color digitalcamera with SPOT Software v. 4.5.9. The hot stage was calibrated usingUSP melting point standards.

Elemental Analysis.

Elemental analysis for carbon, hydrogen, nitrogen and phosphorus wasperformed by Exova, of Santa Fe Springs, Calif.

Example 1

Preparation of Phosphate Salt of α-6-mPEG₆-O-Hydroxycodone

The free base, α-6-mPEG₆-O-hydroxycodone, may be prepared using methodsknown in the art, for example, as described in U.S. Pat. No. 8,173,666.In the examples that follow, mixtures of α-6-mPEG₆-O-hydroxycodone andsolvent were prepared and assessed under various conditions for solidformation. Potential counter ions of a number of acids were tested toassess whether they might form a solid salt withα-6-mPEG₆-O-hydroxycodone. Table 1 below summarizes the acid counterions that were tested.

TABLE 1 Acetic acid L-Lactic acid Phosphoric acid, monolithium saltD-Aspartic Maleic acid Phosphoric acid, monosodium salt L-AsparticR-Mandelic acid Succinic acid Benzoic acid S-Mandelic acid Sulfuric acidCitric acid D-Malic acid D-Tartaric acid R-Camphor-10-sulfonic acidL-Malic acid L-Tartaric acid S-Camphor-10-sulfonic acid Methanesulfonic4-Toluenesulfonic acid acid Ethane-1,2-disulfonic acid Orotic acidToluic Fumaric acid Oxalic acid Trifluoroacteic acid Hydrochloric acidPhosphoric acid

Based on the initial experiments and the properties of the solidsgenerated, phosphoric acid and D-tartaric acid were identified aspotentially viable salt forms. Those salts were prepared according tofollowing methods.

Phosphoric Acid Salt:

To 500 mg of α-6-mPEG₆-O-hydroxycodone dissolved in 2 ml THF was added54 μL of a 14.6M solution of phosphoric acid. To the solution was added2 ml of heptane and a white precipitate formed. The mixture stirred forabout 3 hours. An additional 2 ml of heptane was added and a whiteprecipitate formed. The mixture was stirred for 3 days and theprecipitate was isolate by vacuum filtration, yielding the monophosphatesalt (74% yield). FIG. 1 is an XRPD pattern of the phosphoric acid salt.FIG. 2 is a ¹H NMR of the phosphoric acid salt taken in DMSO. FIG. 3 isa thermogravimetirical analysis (TGA) of the phosphoric acid salt. FIG.4 is a differential scanning calorimetry (DSC) analysis of thephosphoric acid salt. Elemental analysis confirmed the presence ofphosphoric acid in a 1:1 ratio with the free base, indicating amonophosphate salt.

The phosphoric acid salt of α-6-mPEG₆-O-hydroxycodone was also formed ona larger scale by dissolving 902.9 mg of α-6-mPEG₆-O-hydroxycodone in3.6 mL of tetrahydrofuran, resulting in a clear solution following briefsonication. 104 μL of a ˜14.6 M phosphoric acid solution was added, uponwhich white precipitation was observed. 3.6 mL of heptane was added andthe sample was stirred for ˜6.5 hours. An additional 3.6 mL of heptanewas added and the sample was allowed to stir at room temperature forapproximately one day. The resulting solids were isolated by vacuumfiltration using a 0.2 micron nylon filter. The filtration process wasobserved to be slow. The solids were dried in a vacuum oven at ambientfor approximately one day. The calculated yield assuming a 1:1 phosphatesalt formed was approximately 82%. FIG. 5 is an XRPD pattern of thephosphoric acid salt. FIG. 6 is a differential scanning calorimetry(DSC) analysis of the phosphoric acid salt.

D-Tartaric Acid Salt:

To 200 mg of α-6-mPEG₆-O-hydroxycodone dissolved in THF (˜200 mg/mL) wasadded D-tartaric acid solution (˜50.5 mg in 200 μL MeOH, ˜1.7M)dissolved in MeOH (clear solution), 1 mL EtOAc was added (clearsolution), rotary evaporation yielded solids, 1 mL MTBE was added to thesolids and stirred at room temperature for about 1 day. Solidα-6-mPEG₆-O-hydroxycodone D-tartaric acid salt was recovered by vacuumfiltration (yield=˜71%). FIG. 7 is an XRPD pattern of the D-tartaricacid salt. FIG. 8 is a ¹H NMR of the D-tartaric acid salt taken in DMSO.FIG. 9 is a thermogravimetirical analysis (TGA) of the D-tartaric acidsalt. FIG. 10 is a differential scanning calorimetry (DSC) analysis ofthe D-tartaric acid salt.

A focused crystallization screen was performed in an attempt to furthercrystallize those materials.

Example 2 Focused Crystallization Screen

Phosphate Salt:

Twenty experiments were performed in order to search for conditions thatwould provide a further crystalline material of theα-6-mPEG₆-O-hydroxycodone phosphoric acid salt. Experimental conditionsare summarized in Table 2.

TABLE 2 Solvent System Conditions Result Ethyl Acetate (EtOAc) Slurry at~40° C. for ~5 days, Tacky solids, XRPD same as vacuum filtration, blewN₂, FIG. 1 Ethanol Slurry and RT (room — temperature), added EtOAc(ethyl acetate), stirred ~1 day, cloudy solution Toluene Attempted slowcooling at XRPD same as FIG. 1 ~80° C., slurry at ~60° C. for ~5 days,stirred at ~95° C. for ~1 day (viscous material, cloudy), kept at RT for~1 day (viscous, fine solids), vacuum filtered and washed with MTBE,vacuum filtration and vacuum oven for ~2 days Acetone/Heptane (1:1)Slurry at RT for ~4 hr (no Aggregates, XRPD same as visual solids, hazysolution) FIG. 1 added heptane (white ppt), slurry at RT for ~5 daysAcetonitrile/MeOH (9:1) Slow cooling attempt in Aggregates, XRPD same asacetonitrile (ACN) at −60° C. FIG. 1 (cloudy solution), added minimalMeOH (clear solution), slow cooling to RT (slightly hazy) kept inrefrigerator for ~5 days, kept in freezer for ~5 days (slightly hazysolution), no solid, fast evaporation yielded sticky solids, vacuum ovenfor ~2 days Chloroform/Ethyl Acetate Vapor diffusion (solids), — vacuumfiltration, insufficient solids Chloroform/Isopropyl ether Vapordiffusion, few solids XRPD same as FIG. 1 collected Chloroform/heptane(9:1) Vapor diffusion, solids XRPD same as FIG. 1 formed, vacuum ovenfor ~1 day Chloroform/toluene (9:1) Vapor diffusion, solids — formed,vacuum oven for ~1 day EtOH/Heptane (1:29) Slurry at ~60° C. for ~5 daysXRPD same as FIG. 1 EtOH/Hexanes Vapor diffusion (solids), — refrigeratefor ~7 days (fine solids), vacuum filtration Isopropyl alcohol/water(19:1) Stirred, few solids, fast — evaporation, vacuum oven Methanol/1,2Dichloroethane Slow evaporation (tacky XRPD same as FIG. 1 with (9:1)solids) vacuum oven ~1 day additional peak Methanol/tert-butyl methylVapor diffusion, vacuum XRPD same as FIG. 1 ether (MTBE) filtrationMethanol/EtOAc (9:1) Slow evaporation, vacuum — oven for ~1 dayMethanol/EtOAc (9:1) Slow evaporation, vacuum XRPD same as FIG. 1 withoven for ~1 day additional peak THF/water (19:1) Slow cooling attemptfrom XRPD same as FIG. 1 with ~56 to RT (viscous mass), additional peakadded MTBE, stirred for ~4 days (solvent evaporated, tacky solids),added MTBE, stirred for ~1 day, vacuum filtration (slow filtration)

Crystallization techniques included slurrying at ambient and elevatedtemperature, slow cooling, vapor diffusion, slow evaporation, and heatstress experiments. Experiments were designed to be performed overseveral days in order to have the highest chance of crystallization. Themajority of experiments resulted in materials exhibiting the same XRPDpattern as that of FIG. 1. Three experiments (slow evaporation ofmethanol:1,2-dichloroethane (9:1) and methanol:ethyl acetate (9:1), andcooling from tetrahydrofuran:water (19:1) followed by a slurry intert-butyl methyl ether) resulted in material exhibiting the same XRPDpattern, with greater resolution observed for peaks at ˜15.0 and˜17.0°2θ, such that a new broad peak is observed at ˜16°2θ. (FIG. 5).This material is likely the same phosphate salt, but with only slightlymore order. No crystallization experiments resulted materials thatappear to be significantly more crystalline than the starting material.

D-Tartrate Salt (Material B):

Thirteen experiments were performed for the crystallization ofα-6-mPEG₆-O-hydroxycodone D-tartrate salt. Crystallization techniquesincluded slurrying at subambient and elevated temperature, slow cooling,vapor diffusion, slow evaporation, and heat stress experiments.Experimental conditions are summarized in Table 3. All attempts tofurther crystallize the D-tartrate salt resulted in material similar tothat observed in Example 1.

TABLE 3 Solvent System Conditions Result Acetone Slurry, cold room (veryfine No Solid solids), added MTBE (white ppt) stirred in cold room for~3 days (slightly viscous), vacuum filtration (deliquesced) CumeneSlurry at ~80° C. for ~4 h No Solid (solids on wall), moved to −60° C.oil bath, stirred for {grave over ( )}4 days, stirred at ~95° C. for ~1day (viscous clump), stirred at ~110° C. for −2 h (viscous mass), FC atRT (viscous mass) MeOH/1,2 Slow evaporation (sticky XRPD samedichloroethane solids), vacuum oven at RT as FIG. 7 (9:1) morphology for~1 days Nitromethane Slow cooling ~80° C. to RT XRPD same (clearsolution), kept in as FIG. 7 refrigerator for ~1 day (clear solution),partial fast evaporation (slightly hazy solution), kept in refrigeratorfor ~4 days (slightly hazy solution); fast evaporation (tacky solids),vacuum oven at RT for ~1 day THF Slurry, cold room (viscous XRPD samematerial), added heptane as FIG. 7 (white ppt) stirred in cold room for~3 days (cloudy solution), vacuum filtration, blew N₂ (deliquescing,very few tacky solids), vacuum oven at RT for ~3 days Chloroform/ Vapordiffusion, vacuum XRPD same Isopropyl ether filtration, blew N₂ as FIG.7 Chloroform/ Vapor diffusion, vacuum XRPD same EtOAc filtration, blewN₂ as FIG. 7 EtOAc/EtOH Slurry ~50° C. for ~6 days XRPD same (9:1)(viscous material), kept at as FIG. 7 RT for ~2 days (viscous material),added heptane (viscous material), stirred at RT for ~2 days (solids),vacuum filtration, blew N₂ (slightly tacky solids), vacuum oven at RTfor ~3 days MeOH/MTBE Vapor diffusion (solids), XRPD same vacuumfiltration (tacky as FIG. 7 solids), vacuum oven at RT for ~1 dayTHF/Heptane Slurry ~50° C. for −6 days XRPD same (1:9) (solventevaporated), added as FIG. 7 more solvent, stirred at ~50° C. for ~1day, vacuum filtration (slightly tacky solids), blew N₂ “” Heat stress~60° C. for ~6 days “” vacuum oven ~45° C. for ~3 days

Example 3

Large Scale (Kilogram Scale) Preparation of Alpha6-mPEG₆-O-Hydroxycodone Phosphate Salt

A solution of α-6-mPEG₆-O-hydroxycodone was prepared in a mixture ofmethanol and tert-butyl methyl ether (2:1, 2 volumes) at 30° C. Asolution of phosphoric acid (85% aqueous, 1.05 eq) was prepared in amixture of methanol and tert-butyl methyl ether (2:1, 1.2 volumes) at20° C. The solutions were combined, maintaining a temperature of 30-50°C., resulting in the formation of dissolved α-6-mPEG₆-O-hydroxycodonephosphate. This salt solution was adjusted to 40° C., and graduallytransferred over the course of 1-3 hours into a solution of heptanes andtert-butyl methyl ether (4:1, 14 volumes) maintained at 45° C. Duringthe transfer, α-6-mPEG₆-O-hydroxycodone phosphate precipitated from thecombined streams. The resulting slurry was cooled to 20° C. andagitation was ceased, permitting the solids to settle. The supernate wasdecanted, and heptanes (6 volumes) were added to the solids. The solidswere slurried for at least one hour at 30° C., after which the slurrywas cooled to 20° C. Again agitation was ceased, the solids were allowedto settle, and the supernate was decanted. Fresh heptanes were added tothe solids, which were again slurried for at least one hour at 30° C.The slurry was cooled to 20° C., filtered, and washed with freshheptanes (2 volumes). The wet cake was transferred to a vacuum chamberand dried at ambient temperature for at least 48 hours, to affordα-6-mPEG₆-O-hydroxycodone phosphate, as a slightly waxy, hygroscopicpowder, in 90+% yield. A ¹H NMR of the product is listed in FIG. 11. AnXRPD plot of a solid made according to this Example on a 100 g scale isshown in FIG. 16. The solid form prepared according to this Example hasa melting point in the range of about 175-177° C.

Example 4

Large Scale (Gram Scale) Preparation of Alpha 6-mPEG₆-O-HydroxycodoneD-Tartrate Salt

A solution of α-6-mPEG₆-O-hydroxycodone was prepared in tetrahydrofuran(2 volumes) at 20° C. A solution of D-tartaric acid was likewiseprepared in tetrahydrofuran (2 volumes) at 50° C. The solution ofα-6-mPEG₆-O-hydroxycodone was gradually introduced into the solution ofD-tartaric acid, over the course of 30 minutes. The resulting solutionwas stirred for 2 hours, maintaining a temperature at 50° C. Heptanes (6volumes) were introduced over the course of 30 minutes, while continuingto maintain temperature. The product (α-6-mPEG₆-O-hydroxycodoneD-tartrate) precipitates during the heptanes addition. The resultingslurry was stirred for 2 hours at 50° C., and then allowed to coolgradually to 20° C. The slurry was filtered, washed with heptanes (2volumes), and transferred to a desiccating vacuum chamber (containingP₂O₅) to dry at ambient temperature for at least 12 hours. The productwas recovered as a deliquescent white powder in 90+% yield. FIG. 12 is aXRPD pattern of the α-6-mPEG₆-O-hydroxycodone D-tartrate salt preparedaccording to this method.

Example 5 Preparation of Alpha-6-mPEG₆-O-Hydroxycodone Free Base Tablets

Film coated tables comprising α-6-mPEG₆-O-hydroxycodone free base wereprepared as follows. Table 4 below reports the components in each tabletprepared*. The “amount” refers to the amount of a particular componentas listed in Table 4 for the particular trial being described.

TABLE 4 50 mg 50 mg 50 mg 50 mg Tablet Tablet Tablet Tablet Ingredient(mg/tablet) (mg/tablet) (mg/tablet (mg/tablet) Trial # 1 2 3 4 IntraGranular α-6-mPEG₆-O-hydroxycodone free base 50.0 50.0 50.0 50.0 LactoseMonohydrate, NF (Pharmtose ® 450M) 125.0 87.5 87.5 — MicrocrystallineCellulose (Avicel ® PH101) 57.50 154.0 174.0 154.0 Croscarmellosesodium, USP/NF (Ac-Di-Sol ®) 6.25 8.75 8.75 8.75 Dibasic Calciumphosphate anhydrous, — — — 87.5 NF(Fujicalin ®) Citric acid anhydrous —20.0 — 20.0 Polyvinyl pyrolidone, USP (Povidone) — 14.0 14.0 14.0 ExtraGranular Microcrystalline Cellulose (Avicel ® PH102) 50.0 — — — LactoseMonohydrate, NF (Super Tab ®) 50.0 — — — Croscarmellose sodium, USP/NF(Ac-Di-Sol ®) 6.25 8.75 8.75 8.75 Colloidal Silicon Dioxide, USP/NF(Cabosil ® M5) 2.50 3.50 3.50 3.50 Stearic Acid, NF 1.25 — — — Magnesiumstearate (veg. grade) 1.25 3.50 3.50 3.50 Core tablet weight (mg) 350.0350.0 350.0 350.0 Film coating Opadry ® II 85F18422 White 12.5 17..517.5 17.5 Film coated tablet weight (mg) 362.5 367.5 367.5 367.5 Drugloading 13.8 13.6 13.6 13.6 * Tablets of trials 1 and 3 were notprepared due to poor flow properties of the composition

Preparation of Tablet 2 (Trial 2, 50 mg α-6-mPEG₆-O-Hydroxycodone FreeBase):

The amount (i.e. the amount listed in Trial 2 of Table 4) of citric acidwas dissolved in water to form citric acid solution. The amountα-6-mPEG₆-O-hydroxycodone free base was dissolved in citric acidsolution to form an α-6-mPEG₆-O-hydroxycodone free base/citric acidsolution. The amount of polyvinyl pyrolidone (PVP), USP was dissolved inwater to form PVP solution.

The amounts of lactose monohydrate, microcrystalline cellulose, andcroscarmellose sodium, were screened through #20 mesh, transferred tothe bowl of a high shear granulator, and mixed for about five minuteswith impeller on at 250 RPM. While the powders were mixing, the mixturewas granulated with the previously prepared α-6-mPEG₆-O-hydroxycodonefree base/citric acid solution followed by the PVP solution withimpeller at 500 RPM and chopper at 1200 RPM. Additional water was added,with continued kneading, to produce a wet mass of suitable consistency.

The wet granules were then dried in a fluid bed dryer with an inletsetting of 50° C. until loss of drying (LOD) less than 3% is obtained.The dried granules were passed through a #16 mesh screen. The dried andscreened granules were mixed with the quantities of extra granularexcipients (cross carmellose sodium and colloidal silicon dioxide) thatwere pre-screened through #20 mesh for twelve minutes in a V blender.The quantity of magnesium stearate was screened through #40 mesh andadded to contents in V blender and mixed for three minutes to form finalblend for tablet compression.

The final blend is compressed on a rotary tablet press at a targetweight of 350 mg to result into core tablets having hardness of ˜12 Kp,friability of 0.113%, and disintegrating of ˜14 minutes.

A 20% w/w film coating dispersion solution was prepared and sprayed ontocore tablets in a perforated film coating pan to a theoretical weightgain of ˜5%. The tablets were cooled to room temperature and dischargedfrom coating pan into bulk containers. The film coated tablets weretested for assay, drug dissolution, and content uniformity. Results ofcoated tablet testing are summarized below in Table 5.

TABLE 5 TESTING OF 50 MG ALPHA-6-MPEG₆-O-HYDROXYCODONE FREE BASE FILMCOATED TABLET 2 Tablet 2 Attribute Assay 102.8  Content Uniformity (n =10) Mean: 99.2%; % RSD: 1.6 Range: 96.2-101.7 Dissolution¹ (n = 6) %mean dissolved at 5 minutes 12.1 % mean dissolved at 10 minutes 32.6 %mean dissolved at 15 minutes 53.4 % mean dissolved at 30 minutes 95.3¹Dissolution Conditions: 0.1N HCl, 900 ml, Type II (paddle) apparatus,50 RPM

Preparation of Tablet 4 (50 mg α-6-mPEG₆-O-Hydroxycodone Free Base):

The amount (i.e. the amount listed in Trial 4 of Table 4) of polyvinylpyrolidone (PVP) was dissolved in water to form PVP solution. The amountof citric acid was dissolved in water to form citric acid solution. Theamount of α-6-mPEG₆-O-hydroxycodone free base was dissolved in citricacid solution to form an α-6-mPEG₆-O-hydroxycodone free base/citric acidsolution.

The amounts of dibasic calcium phosphate anhydrous, microcrystallinecellulose, and croscarmellose sodium, were screened through #20 mesh,transferred to the bowl of a high shear granulator, and mixed for fiveminutes with impeller on at 250 RPM. While the powders were mixing, themixture was granulated with previously preparedα-6-mPEG₆-O-hydroxycodone free base-citric acid solution followed by thePVP solution with impeller at 500 RPM and chopper at 1200 RPM.Additional water was added, with continued kneading, to produce a wetmass of suitable consistency.

The wet granules were then dried in a fluid bed dryer with an inletsetting of 50° C. until loss of drying (LOD) less than 3% was obtained.The dried granules were passed through a #16 mesh screen. The dried andscreened granules were mixed with the quantities of extra granularexcipients (cross carmellose sodium and colloidal silicon dioxide) thatwere pre-screened through #20 mesh for twelve minutes in a V blender.The quantity of magnesium stearate was screened through #40 mesh andadded to contents in V blender and mixed for three minutes to form finalblend for tablet compression.

The final blend was compressed on a rotary tablet press at a targetweight of 350.0 mg to result in core tablets having hardness of ˜6 Kp,friability of 0%, and disintegration time of ˜8 minutes.

A 20% w/w film coating dispersion solution was prepared and sprayed ontocore tablets in a perforated film coating pan to a theoretical weightgain of ˜5%. The tablets were cooled to room temperature and dischargedfrom coating pan into bulk containers. The film coated tablets weretested for assay, drug dissolution, and content uniformity. Results ofcoated tablets testing are summarized below in Table 6.

TABLE 6 TESTING OF 50 MG ALPHA-6-MPEG₆-O-HYDROXYCODONE FREE BASE FILMCOATED TABLET 2 Tablet 4 Attribute Assay 102.1  Content Uniformity (n =10) Mean: 100.6%; % RSD: 1.2 Range: 98.8-102.7 Dissolution¹ (n = 6) %mean dissolved at 5 minutes 25.9 % mean dissolved at 10 minutes 66.3 %mean dissolved at 15 minutes 91.1 % mean dissolved at 30 minutes 99.0¹Dissolution Conditions: 0.1N HCl, 900 ml, Type II (paddle) apparatus,50 RPM

Example 6 Preparation of Solid Alpha-6-mPEG₆-O-Hydroxycodone PhosphateSalt Tablets

Film coated tablets comprising solid α-6-mPEG₆-O-hydroxycodone phosphatewere prepared as follows. The solid α-6-mPEG₆-O-hydroxycodone phosphateincludes the solid α-6-mPEG₆-O-hydroxycodone phosphate salt formsdescribed herein. Table 7 below reports the components in each tabletprepared. The “amount” refers to the amount of each component listed inTable 7 for each referenced tablet.

TABLE 7 100 mg 200 mg 400 mg Tablet Tablet Tablet Ingredient (mg/tablet)(mg/tablet) (mg/tablet Trial # 1 2 3 Intra Granular solid α-6-mPEG₆-O-116.25 232.50 465.00 hydroxycodone (100.00) (200.00) (400.00) phosphate(free base) Dibasic Calcium phosphate 223.54 223.54 223.54 anhydrous,NF(Fujicalin ®) Microcrystalline 418.91 302.66 0.00 Cellulose (Avicel ®PH101) Croscarmellose sodium, 33.04 33.04 32.40 USP/NF (Ac-Di-Sol ®)Colloidal Silicon Dioxide, 27.13 54.25 108.50 USP/NF (Cabosil ® M5)Polyvinyl pyrolidone, 40.00 19.72 19.36 USP (Povidone) Extra GranularMicrocrystalline Cellulose 208.61 211.77 0.00 (Avicel ® PH102) DibasicCalcium phosphate 0.00 0.00 223.54 anhydrous, NF(Fujicalin ®) Citricacid monohydrate, NF 40.00 80.00 160.00 Croscarmellose sodium, USP/NF16.20 16.20 32.40 (Ac-Di-Sol ®) Colloidal silicon dioxide, 13.16 13.1615.50 USP/NF (Cabosil ® M5) Magnesium stearate (veg. grade) 13.16 13.1615.50 Core tablet weight (mg) 1150.00 1200.00 1295.74 Film coatingOpadry ® II 85F105039 Blue 46.00 48.00 51.83 Film coated tablet weight(mg) 1196.00 1248.00 1347.57 Drug loading (as salt) 9.7% 18.6% 34.5%Drug loading (as free base) 8.4% 16.0% 29.7%

100 mg α-6-mPEG₆-O-Hydroxycodone Phosphate Tablets (Trial 1):

The amount of polyvinyl pyrolidone (PVP) was dissolved in water to forma PVP solution. The amounts of solid α-6-mPEG₆-O-hydroxycodone phosphatesalt were screened through #14 mesh screen and transferred to the bowlof a high shear granulator. Dibasic calcium phosphate anhydrous,microcrystalline cellulose, croscarmellose sodium, and colloidal silicondioxide were screened through #20 mesh and transferred to the bowl of ahigh shear granulator. The contents in the bowl of the high sheargranulator were mixed for five minutes with impeller on at 250 RPM.While the powders were mixing, the mixture was granulated with thepreviously prepared PVP solution with an impeller at 500 RPM and chopperat 1200 RPM. Additional water was added, with continued kneading, toproduce a wet mass of suitable consistency.

The wet granules were then dried in a fluid bed dryer with an inletsetting of 50° C. until loss of drying (LOD) less than 3% is obtained.The dried granules were passed through a #16 mesh screen. The dried andscreened granules were mixed with the quantities of extra granularexcipients (microcrystalline cellulose, citric acid monohydrate, crosscarmellose sodium, and colloidal silicon dioxide) that were pre-screenedthrough #20 mesh for twelve (12) minutes in a V blender. The quantity ofmagnesium stearate was screened through #40 mesh and added the contentsin V blender and mixed for three minutes to form the final blend fortablet compression.

The final blend was compressed on a rotary tablet press at a targetweight of 1150.0 mg to result into core tablets having hardness of ˜19Kp, friability of 0.07%, and disintegration time of ˜9 min.

A 20% w/w film coating dispersion was prepared and sprayed onto the coretablets in a perforated film coating pan to a theoretical weight gain of˜4%. The tablets were cooled to room temperature and discharged fromcoating pan into bulk containers. The film coated tablets were testedfor assay, drug dissolution, and content uniformity. Results of coatedtablet testing are summarized below in Table 8.

TABLE 8 TESTING OF FILM COATED 100 MG ALPHA-6- MPEG₆-O-HYDROXYCODONEPHOSPHATE TABLETS 100 mg Tablets Attribute Assay 99.4% ContentUniformity (n = 10) Mean; % RSD 99.7%; 1.3% Range 98.1-101.9%Dissolution¹ (n = 6) mean dissolved at 5 minutes 23.8% mean dissolved at10 minutes 60.2% mean dissolved at 15 minutes 80.5% mean dissolved at 30minutes 85.6% mean dissolved at 45 minutes 86.9% mean dissolved at 60minutes 88.3% ¹Dissolution Conditions: 0.1N HCl, 900 ml, Type II(paddle) apparatus, 50 RPM

200 mg α-6-mPEG₆-O-Hydroxycodone Phosphate Tablets (Trial 2):

The amount of polyvinyl pyrolidone (PVP) was dissolved in water to forma PVP solution. The amount of solid α-6-mPEG₆-O-hydroxycodone phosphatesalt was screened through #14 mesh screen and transferred to the bowl ofhigh shear granulator. Dibasic calcium phosphate anhydrous,microcrystalline cellulose, croscarmellose sodium, and colloidal siliconsioxide were screened through #20 mesh and transferred to the bowl of ashigh shear granulator. The contents in the bowl of the high sheargranulator were mixed for five minutes with an impeller on at 250 RPM.While the powders were mixing, the mixture was granulated with thepreviously prepared PVP solution with the impeller at 500 RPM andchopper at 1200 RPM. Additional water was added, with continuedkneading, to produce a wet mass of suitable consistency.

The wet granules were then dried in a fluid bed dryer with an inletsetting of ˜50° C. until loss of drying (LOD) less than 3% was obtained.The dried granules were passed through a #16 mesh screen. The dried andscreened granules were mixed with quantities of extra granularexcipients (microcrystalline cellulose, citric acid monohydrate, crosscarmellose sodium, and colloidal silicon dioxide) that were pre-screenedthrough #20 mesh for twelve minutes in a V blender. The quantity ofmagnesium stearate was screened through #40 mesh and the contents wereadded in V blender and mixed for three minutes to form final blend fortablet compression.

The final blend was compressed on a rotary tablet press at a targetweight of 1200.0 mg to result into core tablets having hardness of ˜19Kp, friability of 0.06%, and disintegration time of ˜8 min.

A 20% w/w film coating dispersion was prepared and sprayed onto the coretablets in a perforated film coating pan to a theoretical weight gain of˜4%. The tablets were cooled to room temperature and discharged fromcoating pan into bulk containers. The film coated tablets were testedfor assay, drug dissolution, and content uniformity. Results of coatedtablet testing are summarized below in Table 9.

TABLE 9 TESTING OF FILM COATED200 MG ALPHA-6- MPEG₆-O-HYDROXYCODONEPHOSPHATE TABLETS 200 mg Tablets Attribute Assay 99.3% ContentUniformity (n = 10) Mean; % RSD 97.8%; 1.2% Range 95.7-99.8%Dissolution¹ (n = 6) mean dissolved at 5 minutes 18.6% mean dissolved at10 minutes 54.7% mean dissolved at 15 minutes 75.0% mean dissolved at 30minutes 87.9% mean dissolved at 45 minutes 89.6% mean dissolved at 60minutes 90.9% ¹Dissolution Conditions: 0.1N HCl, 900 ml, Type II(paddle) apparatus, 50 RPM

400 mg α-6-mPEG₆-O-Hydroxycodone Phosphate Tablets (Trial 3):

The amount of polyvinyl pyrolidone (PVP) was dissolved in water to forma PVP solution. The amount of solid α-6-mPEG₆-O-hydroxycodone phosphatesalt were screened through #14 mesh screen and transferred to the bowlof a high shear granulator. Dibasic calcium phosphate anhydrous,croscarmellose sodium, and colloidal silicon dioxide were screenedthrough #20 mesh and transferred to the bowl of a high shear granulator.The contents in the bowl of high shear granulator were mixed for fiveminutes with impeller on at 250 RPM. While the powders were mixing, themixture was granulated with the previously prepared PVP solution withimpeller at 500 RPM and chopper at 1200 RPM. Additional water was added,with continued kneading, to produce a wet mass of suitable consistency.

The wet granules were then dried in a fluid bed dryer with an inletsetting of ˜50° C. until loss of drying (LOD) less than 3% is obtained.The dried granules were passed through a #16 mesh screen. The dried andscreened granules were mixed with the quantities of extra granularexcipients (dibasic calcium phosphate anhydrous, citric acidmonohydrate, cross carmellose sodium, and colloidal silicon dioxide)that were pre-screened through #20 mesh for twelve minutes in a Vblender. The quantity of magnesium stearate was screened through #40mesh and added to contents in V blender and mixed for three minutes toform final blend for tablet compression.

The final blend was compressed on a rotary tablet press at a targetweight of 1295.7 mg to result into core tablets having hardness of ˜18Kp, friability of 0.04%, and disintegration time of ˜12 min.

A 20% w/w film coating dispersion was prepared and sprayed onto the coretablets in a perforated film coating pan to a theoretical weight gain of˜4%. The tablets were cooled to room temperature and discharged fromcoating pan into bulk containers. The film coated tablets were testedfor assay, drug dissolution, and content uniformity. Results of coatedtablet testing are summarized below in Table 10.

TABLE 10 TESTING OF FILM COATED 400 MG ALPHA-6- MPEG₆-O-HYDROXYCODONEPHOSPHATE TABLETS 400 mg Tablets, Attribute Assay 95.0% ContentUniformity (n = 10) Mean; % RSD 96.6%; 3.4% Range 91.5-102.8%Dissolution¹ (n = 6) mean dissolved at 5 minutes  9.0% mean dissolved at10 minutes 28.6% mean dissolved at 15 minutes 47.6% mean dissolved at 30minutes 88.0% mean dissolved at 45 minutes 97.2% mean dissolved at 60minutes 99.4% ¹Dissolution Conditions: 0.1N HCl, 900 ml, Type II(paddle) apparatus, 50 RPM

As reported in Table 7, tablets comprising solidα-6-mPEG₆-O-hydroxycodone phosphate have been prepared that have a drugloading of at least about 34.5 percent (Table 7, Trial 3). While tabletswere prepared using the free base of α-6-mPEG₆-O-hydroxycodone, themaximum drug loading for those tablets was about 14 percent. Tablets ofdifferent weights with drug loadings similar to those of Table 7, Trial3, may be prepared in a similar manner. As such, use of the solidα-6-mPEG₆-O-hydroxycodone phosphate salt in tablets results in anincreased drug loading. Practical implications of an increased drugloading are understood to those of skill in the art and include, amongother things, a reduced tablet size, reduced cost of goods, andincreased throughput. Reduced tablet size may also help with patientcompliance. Further, the reduction in size may allow for the addition ofother beneficial excipients.

Example 7

Alternative Preparation of Alpha 6-mPEG₆-O-Hydroxycodone Phosphate Salt

27.22 g of freebase alpha-6-mPEG₆-O-hydroxycodone was added to a 250 mLjacketed flask. The flask was equipped with a nitrogen inlet, mechanicalstirrer and temperature probe connected to a digital read-out. 163 mL oftBME (methyl tert-butyl ether):heptane (5:1 vol:vol) was added to make ahomogeneous solution at 15° C. Aqueous phosphoric acid (3103 μL of 85+%)was added over 1 hr at 10 minutes intervals. During the first addition,the initially formed solids were long strings and agitation helped totransform fine solid in matter of seconds. Exothermic temperature spikesoccurred; the range of these increases was 8-10° C. observed during theinitial 5 added portions. During the 6th and 7th added portion thetemperature spike was reduced substantially to increments of a Celsiusdegree. After 2 hours the slurry was filtered. The filtration rate wasinstantaneous with no solvent retention. The wet cake was washed with 90mL tBME (2×45 mL) and set to dry at ambient temperature overnight insidea vacuum oven. The isolated 30.57 g of white solid (96.5% isolatedyield) was filtered. The solid after delumping with spatula was freeflowing. The % LOD of the wet cake was at 43.2%. HPLC purity was at98.6%. Bulk density was 0.3276 g/mL, tap density was 0.3931 g/mL, andthe Hausner ratio was 1.20. XRPD conformed to the salt preparedaccording to Example 3. FIG. 16 depicts various XRPD scans for the saltprepared according to Example 7 on a 30 g, 100 g, and 520 g scale and asalt prepared according to Example 3 on a 100 g scale. XRPD patternswere obtained using a Bruker D8 Advance equipped with a Cu Kα radiationsource (1.54 Å), a 9-position sample holder and a LYNXEYE Super SpeedDetector. Typically, the duration of each scan was 180 seconds and the2θ range was 4 to 40°. Samples were placed on zero-background, siliconplate holders. Additional characteristics of the salts preparedaccording to the present Example are listed in Table 11. DSC data werecollected using a TA Instruments Q10 DSC. Typically, samples (˜2 mg)were placed in hermetic alodined aluminum sample pans and scanned from30 to 350° C. at a rate of 10° C./min under a nitrogen purge of 50mL/min. A Malvern Hydro 2000 SM (A) Mastersizer was used for particlesize analysis data using a generic method. Ethyl acetate was used as thedispersant, with a pump speed of 2000 rpm, obstruction of 10-15%. Theaddition style included direct addition of the solid to the dispersantuntil desired obstruction is achieved. The number of measurements was aminimum of two. For PSD analysis, a sample was taken from the bulk ofthe solid. FIGS. 13, 14, and 15 are plots of the PSD analysis for the 30g, 100 g, and 520 g lots respectively.

TABLE 11 Physical Characterization 30 g Lot 100 g Lot 520 g Lot HPLCAnalysis 98.6% 98.1% 98.7% DSC, Onset and Peak, ° C. 176.6, 179.8 175.9,178.6 177.3, 178.9 Karl Fisher Titration (wt %) 1.6  1.8  2.1  TapDensity 0.39 g/mL 0.48 g/mL 0.49 g/mL Bulk Density 0.33 g/mL 0.37 g/mL0.39 g/mL Hausner ratio 1.18 1.30 1.25 Water Vapor Sorption  4.2%  4.1% 4.2% (gain between 0-50% RH) Particle Size Distribution DV[10] = 7 μm DV[10] = 9 μm  DV[10] = 7 μm  DV[50] = 47 μm DV[50] = 53 μm DV[50] = 47μm DV[90] = 92 μm  DV[90] = 109 μm DV[90] = 93 μm

While previous examples, e.g. Examples 1 and 3, provide a suitable solidphosphate salt, the process of Example 7 produces a crystalline solidthat has beneficial characteristics over those previously prepared. Forexample, the particle size distribution of the solids produced with thepresent example is narrower than that of solids produced according toExample 3 (See FIG. 17, which compares the PSD of the 30 g example above(Ex. 7) with the process of Example 3). Additionally, the process ofExample 3 results in partial oiling of the solid salt, which in turnmade the solid salt have waxy characteristics. Additionally, the solidsheld methanol which may result in extended drying time (in certaincases, up to 7 to 14 days). Furthermore, the previous process alsoincluded decantation during the process which can present challenges ona large scale.

In contrast, the process described in the above Example is relativelysimple and short. Water was also found to play a role in the solidformation. Water content in the reaction mixture is about 0.4-0.8 wt %,from the aqueous phosphoric acid. The resulting solid is powder likewith low tendency of agglomeration upon storage. Compared with theprocess of Example 3, the product of the new process is more powder likeand is more resistant to forming chunks.

Example 8 Preparation of Solid Alpha-6-mPEG₆-O-Hydroxycodone PhosphateSalt Tablets

Film coated tablets comprising solid α-6-mPEG₆-O-hydroxycodone phosphateprepared according to Example 7 were prepared as follows. Table 12 belowreports the components and amount used for the initial blend.

TABLE 12 Batch Actual Quantity (g) Percent Amount Actual Ingredient(Target) (Target) (g) Percent solid α-6-mPEG₆-O- 871.875 29.54 872.0029.53 hydroxycodone phosphate (free base) Dibasic Calcium 712.500 24.14712.64 24.14 phosphate anhydrous, NF(Fujicalin ®) Microcrystalline1078.125 36.53 1078.14 36.52 Cellulose (Avicel ® PH102) Croscarmellose127.500 4.32 127.51 4.32 sodium, USP/NF (Ac-Di-Sol ®) Colloidal Silicon131.250 4.45 131.83 4.47 Dioxide, USP/NF (Cabosil ® MP5) Magnesiumstearate, NF 30.000 1.02 30.01 1.02 Total Weight 2951.25 2952.13 Filmcoating Opadry II White 118.050 4.00 — 85F18520 (12% Titanium Dioxide)Purified water USP Q.S. Q.S. Total Weight 3069.3 Drug loading (as salt)29.54% 29.54% 29.53

A blend was prepared using the actual amounts set forth in Table 12. Thesolid form of α-6-mPEG₆-O-hydroxycodone phosphate, microcrystallinecellulose, and colloidal silicone dioxide were sieved through a mesh #20sieve and blended using a 4/16 Quart shell V-blender for 15 minutes(Preblend 1). Dibasic calcium phosphate and croscarmellose sodium weresieved through a mesh #20 sieve and transferred with Preblend 1 andblended in 4/16 quart V blender shell and blend it for 15 minutes.Magnesium stearate was sieved through a mesh #40 and added to theblender. The mixture was blended in the 4/16 quart V-blender shell for 3minutes. The granules formed had a bulk volume of 100 cm³, a tappedvolume of 84 cm³, a bulk density of 0.353 g/cm³, a tapped density of0.420 (g/cm³) and a compressibility index of 15.95%. The appropriateweight of blended granules for each tablet (target dose of 50 mg, 100mg, 200 mg) was measured into a tablet machine and tablets were formed.Opadry II White 85F18520 was weighed and prepared for coating accordingto the manufacturer's instructions (dispersion in water). Tablets weresprayed the dispersion until the target weight gain of 4.00% w/w wasachieved. Tablets were allowed to cool to room temperature. Table 13reports data associated with the various tablets made from the blendabove (sd=standard deviation).

TABLE 13 50 mg Tablet 100 mg Tablet 200 mg Tablet Core Tablet Weight(avg) 196.1 mg (sd = 4.4) 394.7 mg (sd = 6.7) 790.6 mg (sd = 9.9)Thickness (avg) 4.18 mm (sd = 0.01) 4.56 mm (sd = 0.03) 6.5 mm (sd =0.01) Hardness (avg) 6.1 Kp (sd = 0.4) 10.0 Kp (sd = 0.36) 16.00 Kp (sd= 0.46) Disintegration 2:11 (min:sec, sd = 0:31) 2:58 (min:sec, sd =0:34) 1:42 (min:sec, sd = 0:34) (900 ml H20, 37° C.) Friability 0.05%0.05% 0.011%  Coated Tablet Weight (avg) 203.9 mg (sd = 4.3) 404.6 mg(sd = 7.4) 812.2 mg (sd = 8.3) Thickness (avg) 4.24 mm (sd = 0.02) 4.61mm (sd = 0.06) 6.64 mm (sd = 0.02) Hardness (avg) 8.1 Kp (sd = 0.56)12.6 Kp (sd = 0.44) 19.4 Kp (sd = 1.15) Assay 99.2% 99.8% 97.1% Contentuniformity 98.5 ± 1.6 97.7 ± 1.7 97.5 ± 0.2 (n = 10) RSD 1.62% 1.73%1.21% Range 96.8%-101.2% 95.4%-100.2% 95.8%-100.2%

Dissolution data for the tablets prepared as described above arereported in Table 14 below. The dissolution conditions were 0.1N HCl,900 mL, Type II (paddle) apparatus, 50 RPM.

TABLE 14 Time % Dissolved % Dissolved % Dissolved (min) (50 mg tablet)(100 mg tablet) (200 mg tablet) 5 43.7 (sd = 9.0)  33.2 (sd = 13.3) 21.2(sd = 9.0) 10 94.4 (sd = 2.5) 77.1 (sd = 7.8) 60.4 (sd = 2.5) 15 95.7(sd = 2.5) 91.6 (sd = 2.5) 82.7 (sd = 2.5) 30 96.5 (sd = 2.0) 92.9 (sd =2.0) 93.1 (sd = 2.0) 45 97.0 (sd = 2.2) 93.8 (sd = 1.8) 93.5 (sd = 2.2)60 98.0 (sd = 1.6) 94.6 (sd = 1.9) 94.1 (sd = 1.6) 90 98.6 (sd = 1.4)96.0 (sd = 1.9) 95.3 (sd = 1.4) 120 98.4 (sd = 1.2) 96.7 (sd = 1.7) 96.2(sd = 1.2) Inf 98.5 (sd = 1.0) 98.0 (sd = 1.5) 98.9 (sd = 1.0)

Example 9 Preparation of Solid Alpha-6-mPEG₆-O-Hydroxycodone PhosphateSalt Tablet

Film coated tablets comprising solid α-6-mPEG₆-O-hydroxycodone phosphateprepared according to Example 7 were prepared as follows. Table 14 belowreports the components and the targeted amount of each component in thebatch and tablets prepared. The actual amounts may slightly vary fromthe target values.

TABLE 14 1300 mg Batch Tablet Quantity Ingredient (mg/tablet) (g) IntraGranular solid α-6-mPEG₆-O- 465.00 250.38 hydroxycodone phosphateDicalcium Phosphate, NF 444.00 239.08 Microcrystalline Cellulose, NF219.00 117.92 Croscarmellose sodium, NF 32.00 17.23 Colloidal silicondioxide NF 54.00 29.08 Povidone, USP 23.00 12.38 Purified Water, USP**Q.S. Q.S. Total 1237.00 666.07 Extra Granular Croscarmellose sodium,USP/ 32.00 17.23 NF (Ac-Di-Sol ®) Colloidal silicon dioxide, USP/ 15.508.35 NF (Cabosil ® MP5) Magnesium stearate 15.50 8.35 Core tablet weight(mg) 1300.0 700.00 Film coating Opadry II White 85F18520 52.00 28.00(12% Titanium Dioxide) Purified Water, USP** Q.S. Q.S. Film coatedtablet weight (mg) 1352.0 728.00 Drug loading (as salt) 35.77% 35.77%

Solid α-6-mPEG₆-O-hydroxycodone phosphate was placed through a #14 meshscreen followed by colloidal silicone dioxide, and transferred into ahigh shear granulator. All intragranular excipients (except Povidone)were sieved through a #20 mesh screen, mixed in a V blender for 5minutes and charged into the high shear granulator. The blend was mixedfor 5 minutes with an impeller at (250 rpm) and without chopper. Thepowder blend was granulated using the Povidone solution (water) withimpeller speed of 500 rpm, and the chopper speed of 1200 rpm. The wetgranules were transferred to a fluidized bed processor, and dried at aninlet temperature of about 40-50° C. with airflow of about 0.25-0.55bar. The drying process was continued until the loss on drying (LOD) ofgranules was <3.00% and the dried granules were passed through a #16mesh screen. The appropriate weight of granules was loaded and pressedinto tablets. The Opadry II White 85F18520 was weighed and the coatingdispersion was prepared according to the manufacturer's instructions,which was sprayed onto the tablets until the target weight gain of 4.00%w/w was attained and the tablets were allowed to cool.

Modifications and variations in the subject matter set forth in theabove illustrative examples are expected to occur to those skilled inthe art. Only such limitations as appear in the appended claims shouldbe placed on any claimed invention.

All publications including books, patents, patent applications andpublished patent applications cited herein are hereby incorporated byreference in their entireties for all purposes.

What is claimed is:
 1. A solid salt form of α-6-mPEG₆-O-hydroxycodone.2. The solid salt form of α-6-mPEG₆-O-hydroxycodone of claim 1, whereinthe salt form is a disordered crystalline form.
 3. The solid salt formof α-6-mPEG₆-O-hydroxycodone of claim 1, wherein the salt form is acrystalline form.
 4. The solid salt form of any one of the precedingclaims, wherein the solid salt form is α-6-mPEG₆-O-hydroxycodonephosphate salt.
 5. The solid salt form of any one of the precedingclaims, wherein the α-6-mPEG₆-O-hydroxycodone phosphate salt is amonophosphate salt.
 6. The solid salt form of any one of the precedingclaims, wherein the solid salt form has X-ray powder diffraction peakvalues comprising: 2.0±0.2, 15.0±0.2, and 17.0±0.2 degrees two theta,when measured with Cu Kα radiation.
 7. The solid salt form of any one ofthe preceding claims, wherein the solid salt form has X-ray powderdiffraction peak values comprising: 2.0±0.2, 5.5±0.2, 15.0±0.2,17.0±0.2, and 20.5±0.2 degrees two theta, when measured with Cu Kαradiation.
 8. The solid salt form of any one of the preceding claims,wherein the solid salt form has X-ray powder diffraction peak valuescomprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2degrees two theta, when measured with Cu Kα radiation.
 9. The solid saltform of any one of the preceding claims, wherein the solid salt form hasX-ray powder diffraction peak values comprising: 2.0±0.2, 4.5±0.2,5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2,17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2,28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kαradiation.
 10. The solid form of any one of the preceding claims,wherein the solid salt form has at least one X-ray powder diffractionpeak values selected from the group comprising: 2.0±0.2, 5.5±0.2,6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2,20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation.
 11. The solid form of any one of thepreceding claims, wherein the solid salt form has at least two X-raypowder diffraction peak values selected from the group comprising:2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degreestwo theta, when measured with Cu Kα radiation.
 12. The solid form of anyone of the preceding claims, wherein the solid salt form has at leastthree X-ray powder diffraction peak values selected from the groupcomprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2degrees two theta, when measured with Cu Kα radiation.
 13. The solidform of any one of the preceding claims, wherein the solid salt form hasat least four X-ray powder diffraction peak values selected from thegroup comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2,13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2,and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 14.The solid form of any one of the preceding claims, wherein the solidsalt form has at least five X-ray powder diffraction peak valuesselected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2,11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2,28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kαradiation.
 15. The solid form of any one of the preceding claims,wherein the solid salt form has at least six X-ray powder diffractionpeak values selected from the group comprising: 2.0±0.2, 5.5±0.2,6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2,20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation.
 16. The solid form of any one of thepreceding claims, wherein the solid salt form has at least seven X-raypowder diffraction peak values selected from the group comprising:2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2,17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degreestwo theta, when measured with Cu Kα radiation.
 17. The solid form of anyone of the preceding claims, wherein the solid salt form has at leasteight X-ray powder diffraction peak values selected from the groupcomprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2degrees two theta, when measured with Cu Kα radiation.
 18. The solidform of any one of the preceding claims, wherein the solid salt form hasat least nine X-ray powder diffraction peak values selected from thegroup comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2,13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2,and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 19.The solid form of any one of the preceding claims, wherein the solidsalt form has at least ten X-ray powder diffraction peak values selectedfrom the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2,13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2, 28.5±0.2,and 29.5±0.2 degrees two theta, when measured with Cu Kα radiation. 20.The solid form of any one of the preceding claims, wherein the solidsalt form has at least eleven X-ray powder diffraction peak valuesselected from the group comprising: 2.0±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2,11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2, 20.5±0.2, 25.0±0.2,28.5±0.2, and 29.5±0.2 degrees two theta, when measured with Cu Kαradiation.
 21. The solid form of any one of the preceding claims,wherein the solid salt form has at least twelve X-ray powder diffractionpeak values selected from the group comprising: 2.0±0.2, 5.5±0.2,6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2, 15.0±0.2, 17.0±0.2, 19.5±0.2,20.5±0.2, 25.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation.
 22. The solid form of any one of thepreceding claims, wherein the solid salt form has at least thirteenX-ray powder diffraction peak value selected from the group comprising:2.0±0.2, 4.5±0.2, 5.5±0.2, 6.5±0.2, 8.5±0.2, 11.0±0.2, 13.0±0.2,15.0±0.2, 17.0±0.2, 17.5±0.2, 19.5±0.2, 20.5±0.2, 21.5±0.2, 24.0±0.2,25.0±0.2, 26.0±0.2, 28.5±0.2, and 29.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation.
 23. The solid salt form of any one of thepreceding claims, wherein the solid salt form has X-ray powderdiffraction two theta peak values substantially similar to those ofFIG.
 1. 24. The solid salt form of any one of the preceding claims,wherein the solid salt form has X-ray powder diffraction two theta peakvalues substantially similar to any one of those of FIG.
 16. 25. Thesolid salt form of any one of the preceding claims, wherein theα-6-mPEG₆-O-hydroxycodone phosphate salt exhibits a first broadendothermic peak over a range of about 10° C. to about 140° C.; a secondendothermic peak at about 160° C. to about 164° C. and a thirdendothermic peak at about 170° C. to about 173° C. on a differentialscanning calorimeter.
 26. The solid salt form of any one of thepreceding claims, wherein the solid salt form exhibits an endothermicpeak as measured by a differential scanning calorimeter with an onset ofabout 174° C. to about 179° C. and a peak from about 177° C. to about181° C.
 27. The solid salt form of any one of the preceding claims,wherein the solid salt form exhibits an endothermic peak as measured bya differential scanning calorimeter with an onset of about 175° C. toabout 178° C. and a peak from about 178° C. to about 180° C.
 28. Thesolid salt form of any one of the preceding claims, wherein the solidsalt form has a particle size distribution wherein DV[10] is about 3 μmto about 15 μm; DV[50] is about 40 μm to about 60 μm; and DV[90] isabout 90 μm to about 120 μm.
 29. The solid salt form of any one of thepreceding claims, wherein the solid salt form has a particle sizedistribution wherein DV[10] is about 5 μm to about 13 μm; DV[50] isabout 45 μm to about 55 μm; and DV[90] is about 90 μm to about 115 μm.30. The solid salt form of any one of the preceding claims, wherein thesolid salt form has a particle size distribution wherein DV[10] is about6 μm to about 11 μm; DV[50] is about 45 μm to about 55 μm; and DV[90] isabout 90 μm to about 112 μm.
 31. The solid salt form of any one of thepreceding claims, wherein the solid salt form has a particle sizedistribution wherein DV[10] is about 7 μm to about 9 μm; DV[50] is about47 μm to about 53 μm; and DV[90] is about 92 μm to about 109 μm.
 32. Amethod of preparing the solid form of α-6-mPEG₆-O-hydroxycodonephosphate of any one of the preceding claims, comprising: dissolvingα-6-mPEG₆-O-hydroxycodone free base in a mixture of a first solvent anda second solvent; combining the α-6-mPEG₆-O-hydroxycodone solution witha solution of phosphoric acid in a third solvent and fourth solvent;combining the α-6-mPEG₆-O-hydroxycodone phosphoric acid solution with amixture fifth solvent and a sixth solvent to form a slurry; filteringthe slurry to yield the α-6-mPEG₆-O-hydroxycodone phosphate salt insolid form.
 33. A method of preparing the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate of any one of the preceding claims,comprising: dissolving α-6-mPEG₆-O-hydroxycodone free base in about 2relative volumes of a mixture methanol and tert-butyl methyl ether (2:1ratio of methanol to tert-butyl methyl ether); combining theα-6-mPEG₆-O-hydroxycodone solution with a solution of phosphoric acid inabout 1.2 relative volumes of a mixture methanol and tert-butyl methylether (2:1 ratio of methanol to tert-butyl methyl ether); combining theα-6-mPEG₆-O-hydroxycodone phosphoric acid solution with about 14relative volumes of a mixture of heptanes and tert-butyl methyl ether(4:1 ratio of heptanes to tert-butyl methyl ether) to form a slurry;filtering the slurry to yield the α-6-mPEG₆-O-hydroxycodone phosphatesalt in solid form.
 34. The method of claim 33, wherein theα-6-mPEG₆-O-hydroxycodone phosphoric acid solution is combined with themixture of heptanes and tert-butyl methyl ether over about 1 to about 3hours.
 35. A method of preparing the solid form ofα-6-mPEG₆-O-hydroxycodone phosphate of any one of the preceding claims,comprising dissolving α-6-mPEG₆-O-hydroxycodone free base in a mixtureof tert-butyl methyl ether and heptanes; adding phosphoric acid to forma slurry; stirring the slurry, and filtering to recover the solidα-6-mPEG₆-O-hydroxycodone phosphate salt.
 36. The method of claim 35,wherein the phosphoric acid is added over a time of about 30 minutes toabout 3 hours.
 37. The method of claim 35 or 36, wherein the phosphoricacid is added over about 1 hour.
 38. The method of any one of claims 35to 37, wherein the phosphoric acid is added at about ten minuteintervals over the course of about 30 minutes to about 3 hours.
 39. Themethod of any one of claims 35 to 38, wherein the phosphoric acid isadded at about ten minute intervals over the course of about 1 hour. 40.The method of any one of claims 35 to 39, wherein the solidα-6-mPEG₆-O-hydroxycodone phosphate salt is washed with tert-butylmethyl ether.
 41. The method of any one of claims 35 to 40, wherein theamount of α-6-mPEG₆-O-hydroxycodone free base is “X” kilograms; thevolume of tert-butyl methyl ether is 5*“X” liters; and the volume ofheptanes is “X” liters.
 42. The method of any one of claims 35 to 41,wherein after the phosphoric acid has been added, the solution isallowed to stir for about 1 to about 4 hours.
 43. The method of any oneof claims 35 to 42, wherein after the phosphoric acid has been added,the solution is allowed to stir for about 2 hours.
 44. The method of anyone of claims 35 to 43, wherein the solution ofα-6-mPEG₆-O-hydroxycodone free base is maintained at a temperature ofabout 15° C.
 45. The method of any one of claims 35 to 44, wherein thesolution of α-6-mPEG₆-O-hydroxycodone is maintained at a temperature ofabout 15° C. while the phosphoric acid is being added.
 46. The method ofany one of claims 35 to 45, wherein the solution ofα-6-mPEG₆-O-hydroxycodone is maintained at a temperature of about 15° C.throughout the addition of phosphoric acid.
 47. The method of any one ofclaims 35 to 46, wherein the reaction mixture contains water.
 48. Themethod of any one of claims 35 to 47, wherein the amount of water isabout 0.4-0.8 wt %.
 49. The method of any one of claims 35 to 48,wherein the amount of phosphoric acid is about 0.8 molar equivalents toabout 1.2 molar equivalents.
 50. The method of any one of claims 35 to49, wherein the amount of phosphoric acid is about 0.9 molar equivalentsto about 1.1 molar equivalents.
 51. The method of any one of claims 35to 50, wherein the amount of phosphoric acid is about 1.0 molarequivalents.
 52. The method of any one of claims 35 to 51, wherein thephosphoric acid is an aqueous solution of phosphoric acid.
 53. A solidα-6-mPEG₆-O-hydroxycodone phosphate salt, prepared according to themethod of any one of claims 32 to
 52. 54. A crystalline solidα-6-mPEG₆-O-hydroxycodone phosphate salt, prepared according to themethod of any one of claims 32 to
 52. 55. A disordered crystalline solidα-6-mPEG₆-O-hydroxycodone phosphate salt, prepared according to themethod of any one of claims 32 to
 52. 56. The solid salt form of claim 1or claim 2, wherein the solid salt form is α-6-mPEG₆-O-hydroxycodoneD-tartrate salt.
 57. The solid salt form of claim 56, wherein theα-6-mPEG₆-O-hydroxycodone D-tartrate salt is a monotartrate salt. 58.The solid salt form of claim 56 or claim 57, wherein the solid form ofα-6-mPEG₆-O-hydroxycodone D-tartrate salt has X-ray powder diffractionpeak values comprising: 2.5±0.2 and 15.0±0.2 degrees two theta, whenmeasured with Cu Kα radiation.
 59. The solid salt form of any one ofclaims 56 to 58, wherein the solid form of α-6-mPEG₆-O-hydroxycodoneD-tartrate salt has X-ray powder diffraction peak values comprising:2.5±0.2, 15.0±0.2, 20.0±0.2, and 23.5±0.2 degrees two theta, whenmeasured with Cu Kα radiation.
 60. The solid salt form of any one ofclaims 56 to 59, wherein the solid salt form has X-ray powderdiffraction two theta peak values substantially similar to those of FIG.7 and/or FIG.
 12. 61. A method of preparing the solid form ofα-6-mPEG₆-O-hydroxycodone D-tartrate of any one of claims 1, 2, and 56to 60, comprising: dissolving α-6-mPEG₆-O-hydroxycodone free base in afirst solvent; combining the α-6-mPEG₆-O-hydroxycodone solution with asolution of D-tartaric acid in a second solvent; adding a third solventto the α-6-mPEG₆-O-hydroxycodone D-tartaric acid solution to form aslurry; and filtering the slurry to yield the α-6-mPEG₆-O-hydroxycodoneD-tartrate salt in solid form.
 62. A method of preparing the solid formof α-6-mPEG₆-O-hydroxycodone D-tartrate of any one of claims 1, 2, and56 to 60, comprising: dissolving α-6-mPEG₆-O-hydroxycodone free base inabout 2 relative volumes of tetrahydrofuran; combining theα-6-mPEG₆-O-hydroxycodone solution with a solution of D-tartaric acid ina 2 relative volumes of tetrahydrofuran; adding about 6 equivalents ofheptanes to the α-6-mPEG₆-O-hydroxycodone D-tartaric acid solution toform a slurry; and filtering the slurry to yield theα-6-mPEG₆-O-hydroxycodone D-tartrate salt in solid form.
 63. The methodof claim 62, wherein the heptanes are added to theα-6-mPEG₆-O-hydroxycodone and D-tartaric acid solution over about 30minutes.
 64. A solid α-6-mPEG₆-O-hydroxycodone D-tartrate salt, preparedaccording to the method of any one of claims 61 to
 63. 65. The solidsalt form of any one of claims 56-60 and 64, wherein the solid salt formexhibits a first broad endothermic peak over a range of about 40° C. toabout 110° C. and a second endothermic peak at about 126° C. on adifferential scanning calorimeter.
 66. A method of treating pain in apatient comprising administering a solid salt form ofα-6-mPEG₆-O-hydroxycodone of any one of the preceding claims.
 67. Themethod of claim 66, wherein the pain is moderate to severe pain.
 68. Themethod of claim 66 or 67, wherein the solid salt form ofα-6-mPEG₆-O-hydroxycodone is administered as necessary over a 24 hourperiod to manage moderate to severe pain.
 69. A pharmaceuticalcomposition comprising the solid salt form of α-6-mPEG₆-O-hydroxycodoneof any one of the preceding claims and at least one pharmaceuticallyacceptable excipient.
 70. The pharmaceutical composition of claim 69,wherein the pharmaceutical composition is a tablet.
 71. Thepharmaceutical composition of claim 69 or claim 70, wherein the tabletis a film coated tablet.
 72. The pharmaceutical composition of claim 70or claim 71, wherein the tablet has a loading of the solid salt form ofα-6-mPEG₆-O-hydroxycodone of about 10 percent to about 50 percent. 73.The pharmaceutical composition of any one of claims 70 to 72, whereinthe tablet has a loading of the solid salt form ofα-6-mPEG₆-O-hydroxycodone of about 20 percent to about 50 percent. 74.The pharmaceutical composition of any one of claims 70 to 73, whereinthe tablet has a loading of the solid salt form ofα-6-mPEG₆-O-hydroxycodone of about 30 percent to about 40 percent. 75.The pharmaceutical composition of any one of claims 70 to 74, whereinthe tablet has a loading of the solid salt form ofα-6-mPEG₆-O-hydroxycodone of about 35 percent.
 76. The pharmaceuticalcomposition of any one of claims 70 to 74, wherein the tablet has aloading of the solid salt form of α-6-mPEG₆-O-hydroxycodone of about 30percent.
 77. The pharmaceutical composition of any one of claims 70 to76 wherein the tablet has a friability of less than about 1.0 percent.78. The pharmaceutical composition of any one of claims 70 to 77,wherein the tablet has a friability of less than about 0.10 percent. 79.The pharmaceutical composition of any one of claims 70 to 78, whereinthe tablet has a friability of less than about 0.05 percent.
 80. Thepharmaceutical composition of any one of claims 69 to 79, wherein thesolid salt form of α-6-mPEG₆-O-hydroxycodone isα-6-mPEG₆-O-hydroxycodone phosphate.
 81. The pharmaceutical compositionof any one of claims 69 to 79, wherein the solid salt form ofα-6-mPEG₆-O-hydroxycodone is α-6-mPEG₆-O-hydroxycodone tartrate.
 82. Thepharmaceutical composition of any one of claims 69 to 81, wherein thecomposition comprises about 5 mg to about 1000 mg of the solid salt formof α-6-mPEG₆-O-hydroxycodone.
 83. The pharmaceutical composition of anyone of claims 69 to 82, wherein the composition comprises about 50 mg toabout 500 mg of the solid salt form of α-6-mPEG₆-O-hydroxycodone. 84.The pharmaceutical composition of any one of claims 69 to 83, whereinthe composition comprises one of more excipients selected from the groupcomprising dibasic calcium phosphate, microcrystalline cellulose,croscarmellose sodium, colloidal silicon dioxide, and magnesiumstearate.
 85. The pharmaceutical composition of any one of claims 69 to84, the excipients comprise dibasic calcium phosphate, microcrystallinecellulose, croscarmellose sodium, colloidal silicon dioxide, andmagnesium stearate.
 86. The pharmaceutical composition of any one ofclaims 70 to 85, wherein the tablet comprises intragranular andextragranular components.
 87. The pharmaceutical composition of any oneof claims 70 to 85, wherein the tablet comprises intragranularcomponents.
 88. A method of treating pain in a patient, comprisingadministering the pharmaceutical composition of any one of claims 69 to87.
 89. The method of claim 88, wherein the pain is moderate to severepain.
 90. The method of claim 90 or 89, wherein the composition isadministered as necessary over a 24 hour period to manage moderate tosevere pain.
 91. A method of preparing free flowing solid granulescomprising α-6-mPEG₆-O-hydroxycodone or a solidα-6-mPEG₆-O-hydroxycodone phosphate salt form.
 92. The solid salt formof any one of the preceding claims, having a purity of at least about90%.
 93. The solid salt form of any one of the preceding claims, havinga purity of at least about 95%.